(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/169173 Al 12 November 2015 (12.11.2015) P O P C T
(51) International Patent Classification: (74) Agent: CHINA SINDA INTELLECTUAL PROPERTY A61K 31/56 (2006.01) A61P 3/04 (2006.01) LTD.; B l 1th Floor, Focus Place, 19 Financial Street, A61P 35/00 (2006.01) A61P 3/06 (2006.01) Xicheng District, Beijing 100033 (CN). A61P 15/12 (2006.01) A61P 19/10 (2006.01) (81) Designated States (unless otherwise indicated, for every A61P 1/16 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/CN20 15/077942 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 30 April 2015 (30.04.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (25) Filing Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 2014 10192569.2 8 May 2014 (08.05.2014) CN (84) Designated States (unless otherwise indicated, for every (71) Applicants: SHANGHAI INSTITUTE OF PLANNED kind of regional protection available): ARIPO (BW, GH, PARENTHOOD RESEARCH [CN/CN]; 2140 Xietu GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Road, Building#2, Room 502, Xuhui District, Shanghai TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 200032 (CN). CHANGZHOU RUIMING PHARMA¬ TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, CEUTICAL COMPANY, LTD [CN/CN]; 1558 North DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Longjiang Road, Changzhou, Jiangsu 213 127 (CN). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: YANG, Jun; 2140 Xietu Road, Building#2, GW, KM, ML, MR, NE, SN, TD, TG). Room 502, Xuhui District, Shanghai 200032 (CN). SHI, Huijuan; 2140 Xietu Road, Building#2, Room 502, Xuhui Published: District, Shanghai 200032 (CN). XU, Wenping; 2140 X i — with international search report (Art. 21(3)) etu Road, Building#2, Room 502, Xuhui District, Shanghai 200032 (CN).
(54) Title: ANORDRIN COMPOSITIONS AND METHODS FOR TREATING DISEASES (57) Abstract: The present invention provides methods and compositions for treating cancer, reducing side effects, and reducing postmenopausal symptoms comprising anordrin or analog thereof (such as anordrin) alone or in combination with at least one other agent selected from the group consisting of tamoxifen, raloxifene or functional equivalent thereof, and an aromatase inhibitor. ANO D COMPOSITIONS AND METHODS FO TREATING DISEASES
5 The invention re te to a d i for the treatment of cancer or other d comprising a of a r iri or analog thereof as a ordrin) alone or n n with agent
0 Estrogen binds to it receptors to regulate UNA transcri ption stimulate cell
proliferation a t l metabolic many tissues during mammalian reproduction and development. Three genes f r estrogenic proteins been
identified, encoding estrogen receptor E ) and | ¾ prot n coupled estrogen receptor ( E ) . i and have similar structural and fa ct na , o ntug activation
5 1 ¾ the nucleus, where t ey d to estrogen response elements (EREs found in the promoters of estrogen-responsive genes. This type of modulation i typically referred to as t e classical estrogen pathway ER- and also regulate diverse biological functions through .membrane-initiated estrogen signaling (MIES), associating with plasma membrane by interaction with their ligand binding domain. The detailed molecular mechanisms of signaling b rnen¾bfane-associated Efts are still unclear. The modulatory effects of estrogen mediated by membrane- ssoc t d receptors cell proliferation, matrix/migration, metabolism and glucose homeostasis have been reviewed (I, 2 Furthermore, studies on E knockout i indicate that ER-a the dominant functional estrogen receptor, as compared t ER . Three transcription variants of EE -4 and 36, have bee found. E R 3 JO lacks the AF- domain and contains partial ligand binding domain. It has been found localized t the cell membrane and ytoso Since ER~ is restricted to modulating IES and was ound to be uniquely expressed n t oxi n re sted cancer cells, such as ; A MB 2 and Heel MIES modulated b membrane-associated E is thought to be responsible for re to anti-estrogen therapy found by s researchers (3,4 Orphan G prote n coupled receptor 30 (G E was found to bind E ( beta d estrogen) (5) and modulate l proliferation, resulting resistance to an i estr gen therapy. However, its physiological ft n t n still a matter of controversy investigators (3) u shown to exhibit cardiovascular metabolic defects, with no effect fertility (6). T GPER may he involved the modulation of e trogen ediaied metabolic signaling. The decreased production of estrogen in postmenopausal women leads to that may adversely affect their of life for decades.. Hormone (estrogen) replacement therapy HRT/ERT has bee utilised to treat these symptoms since the 40s. Studies showing increased risk of breast and cancer, as well thromboembolism morbidity, associated with HRT have lead to a recent decline in its , and postmenopausal symptoms remain a problem for many older women. Selective estrogen receptor (S RM ) have n utilized as treatments to regulate estrogen signaling the 1990s. However, lac of a more complete understanding of the molecular mechanisms involved and interfering cro ss talk between selective with different estrogen receptors have made it difficult to design treatment regimens that avoid the development of drug resistance d serious side effects daring clinical Tamoxifen was marketed as an antagon t of the estrogen c ss al pathway to treat breast cancer patients, and was als reported s agonist of ES - 6, potentially leading to anti-estrogen therapy resistance while stimulating the growth of endometrial epithelium cells, resulting in nd i cancer (7, 8) Raloxifene was marketed as an upgraded version of tamoxifen, having fewer side effects and the advantages of inhibiting cancer cell migration and preventing postmenopausal , such as osteoporosis. raloxifene can still cause serious side effects m to tamoxifen treatment, such thromboembolism and non-alcohol steatohepatitis (NASH) ( , ). The detailed mechanisms responsible for the side effects a s by either raloxifene or tamoxifen are still unclear Ipri avone is a der ative of p yto orn one and it metabolite binds to the ER- LSD with lower affinity than E2 exhibiting reduced estrogenic effects. The metabolites of ipritlavone and isofiavoue show comparable binding affinity and activity with ER j as and they have been utilised in some countries a a medicine to prevent osteoporos . However, their effectiveness was not supported! la at least one clinical trial ( ) . Moreover, potential side effects as seen with traditional HRT are still a concern to some investigators (12). 2 7 -d ethyi A n0r 5 an d tan - 1 -dtol (anordio!) first reported a ti estroge activity by m i in the 1960s ( 3 1.4 } Li, .L e eri ed anordiol using propionic acid to d propiona e an rdrin, AN ) in 5 Anordrin marketed as an antiiertiiiiv medicine using the brand nanie A -53 in Chun beginning Estrogen i known to hormone-induced cancer, and anordrin, a s m estrogen receptor antagonist, n l found ife i n cell growth ( , 1 ) , A s .non-prescription in China, Chinese physicians it as anti-tumor agent for nearly decade under legally licensed conditions. However, results 0 reported for patients during clinical therapy. s clinical an anti-tumor agent was stopped in 998 after the introduction of the clinical trial law in China, and ai of the r clinical dat were never collected studied. The disclosures of all publications, patents, n applications and published patent applications referred to herein are hereb incorporated herein by reference In their entirety . The present application in. one aspect provides a d of treating a cancer n individual comprising ad in tering to the individual: a) a effective amount of n anord n or analog thereof (such as anordrin); a d optionally ) an effective of at. least one other agent selected from 0 the group consisting of tamoxifen., raloxifene or functional equivalent thereof, an an r n a se inhibitor. n some embodiments, these s provided a method of reducing s de effect of eas! one other by anordtin or analog thereof (such as anordrin), comprising administering to the individual effective amount o anordrin or analog thereof h anordrin) in combination with the other agent, wherein t e other agent is selected f m group consisting of tamoxifen, 5 raloxifene or functional equivalent thereof, and an o e inhibitor. In d n the other agent tamoxifen- n m embodiments, the other agent raloxifene or functional equivalent thereof (such raloxife e e or a edo ene) lis. th other en i n a a se ue ana ro ole. some the side effects of i t least one other agent comprise elevated sugar uptake, decreased cellular AT concentrations, or G both some embodiments, the sid effects comprise insulin resistance. In some embodiments according to an t of the embodiments above, the cancer Is selected from the group consisting of r cancer, lung cancer, pancreatic e , gastric cancer, colon cancer, liver cancer, and CLL In so e embodiments, the cancer is resistant to treatment with the other agent ot in combination th or r n or thereof as nord n . e d n to m y one of the above, individual positive for membrane bound estrogen receptor. In so e embodiments, the individual is positive for V or n. e aspect, there is provided d of edw symptom in individual, comprising administering to h individual: a) an effective a of an anordrm or analog thereof (such as anord ); d o n ll effective amount of at least one other agent selected from the group consisting of raloxifene or functional equivalent thereof and an aromatase inhibitor. n so embodiments,, the other agent raloxifene or functional equivalent thereof as raloxifene, asof fene. ba¾edoxifene). embodiments, other a nt is n ar mata e inhibitor, c n r o!e. In the i selected ro m the group consisting of fa liver, insulin resistance, high sugar uptake and/or low cellular ATP concentrations, weight ga n, high triglyceride, and osteoporosis and organ atrophy. In some embodiments according t any one of th embodiments described shove, th an rdr or analo thereof (such ano dr ) nd the other agent are administered: sequentially,. Irs s em odiments the a r n or analog thereof (such as n d n) and the other gem ar ad ste d simultaneously . In so e embodiments according to anv one of the embodiments described above, the individual Is b ro ar . h yet another aspect, there is provided pharmaceutical composition comprising an rdri or analog thereof (such as anord n) and at least other agent selected m the group consisting of tamoxifen, raloxifene or functional equivalent thereof, an ar rn t se inhibitor. In some embodiments, the other agent is tamoxifen. In some embodiments, the other agent is raloxifene or functional equivalent thereof (including for example a xifene l t i ene, or ba^edoxifene). In some embodiments, the other agent an aromatase hibi tor, such as anastro ie . I so e e odi ent , te ph r c tic composition further comprises lipid (such a corn oil). In some embodiments, the pharmaceutical composition further comprises protein (such as casein). ra e the weigh ratio of ordr or analog thereof {m a o ri ) and the other agent in the is about :2 to about 20; 1 (including for about 10:1 to b nt : 0, or about :10 to about 1:1.5)., The pharmaceutical composition be present a unit dosage form, fo example an o a 5 u it dosage i m, such as tablets, p s gels, i (e.g si s solutions, emulsions), powders or other particulates, and forth Also provided of using h p e c l on described herein or treating cancer, reducing side effects, and reducing a described herein. IC These nd other aspects and of th present i w en ion will or apparent from the detailed description and the d claims. t is to be d d that one, or all of the properties of the various described herein be combined to form other embodiments of t e present e i 15 BRIEF DESCRIPTION OF Figure F Anordrin or analog thereof (such as anordrin) does not bind t the ligand binding domain (LBD) of ER (2 i GST-fusion n o l onto beads) resulting n inability to n odulat the estrogen classical pathway. A : The perce t of bound to BD after competition with E2, f n (TAM) or ΑΝ , normalised w th ¾ alone a ter subtracting blank; : 0% SGS AGE stained with c o as ie B ne R250 stowing the GST fusion proteins purified by glutathione beads; C: Gel! shows the expression of Bcl-2 in CF-? ce ls treated by TAM, AND or blank using e blotting and probing with an i-f l 2 antibody;. Gel2 s the amount of a on protein in sample; Gei3 is a longer exposure of Gel I Figure 2 : A ordr n or analog thereof (such n ri rin) blocks ¾ binding to 5 ER - -36 expressed in cells and inhibits MDA-MB-231 cell growth and migration through the distribution of integr onto plasma e figure 2A: Th percent of E2 bound to ER-o 36 expressed i HEK-293 and competed by A D or TAM normalised with blank; Figure 2 : Th expression of £ R- -36 in cells was detected by western blotting with an l R antibody; Figure 2C: AN significantly inhibits 50 M DA MB-2 cell growth (red columns) dependent on Its dosage compared to tamoxifen (TAM) (Woe columns); Figure 2D: and EOF inhibit MDA-MB-23 1 cell growth; .Figure E : 6 Μ A O inhibits MDA-MB-231 cells migration tested by µη transwell; Figure 2F: 6pM [ANO] plus ! ng / EG F] inhibits MDA-MB-231 cells migration tested by 8µ irans e l Figure 2 : [ANO hibits integrit* f¾ distribution plasma in MDA MB 2 cells; Figure 2 i : [ANO] inhibits in egris $ distribution onto plasma membrane m M -? cells. Figure 3: Anordr or a alog thereof ( as or r n ro glucose consumpt n in C cells decreases blood glucose in. i . re A: enhances glucose o un t o in F ce l compared to the inhibition by TAM; 3 : 5 n [ANO] r ot only li of 1µΜ [TAM] o glucose m MCF-7 ceils but d above basal levels; Figure 3C: ANO ig i ar ily decrease blood glucose concentration of female dh dh m e Figure 4 : A ord n o analog thereof s as a ord ) r body s triglyceride in liver o ov e io d (OVX) e or norma mice treated with tamoxifen. Figure A: ANO fi a blocks increased body compared to ipnflavone (IF) in OVX 4B: ANO s ni 1 easily blocks. TA ced body increase; Figure 4C nd Figure 4D: Paraffin sections of that A O can significantly triglyceride accumulation co pared to the dose of IF in liver of OVX mice; Figure 4E Figure 4 ; Paraffin sections of liver show thai A O n significantly decrease the amount of triglyceride ar d no aicohol. stea ohepat ti (NASH) induced tamoxifen (TAM) compared to of I in liver of normal mice; Figure 4G: The de of NASH is i c a ed in l er cel closer to capillary vessels .Figure 5: Auordr or analog thereof (such ar rdrin decreases serum T and viscosity induced b tamoxifen. Figure 6: An rtn or alog thereof (such as a ordri ) (75 Μ) blocks EOF ( I r g ) duced ce l growth i T470 cells gure 7: Anordrin or analog thereof (such as a rdri n) inhibits ep cell growth a d induces phosphorylation of i Figure 8: Anordrin or thereof (such as nordr n) prevents atrophy of uterine and. vagina in ari e i¾ed or tamoxifen treated mice. Figure 9; A ord ia or analog thereof (such as anordrin} causes hypertrophy of endometrial epithelial cells (increased ceil size while retaining no but does not induce endometrial epithelial cel proliferation n mice. Figure 0 ; Co oil and casein formula (column oc) of anordrm or analog thereof s c as snordrin) enhances its activity to prevent atrophy of mice uterus compared to methyl-cellulose colu i ) Figure : A o d t or analog thereof as at ordr n) prevents osteoporosis in ova tomi ed Figure : An rdr n or a thereof (s as anord n) it M i s ¾ - binding to and G ! fusion proteins d E ~2¾ cells. Figure 13: Effects of t and anordrin or ano dr n analog (such as anordrin) on cel growth, stroget -eo ro d g and their t ttons with the insulin pathway. A . C of anordin or tamoxifen lor inhibiting growth of M F 7 cells rsd r g conditions with or without insulin in the media.. n of m m in the media c sensistiviry o M.CF-7 cells to t bu increases sensitivity of MCF-7 cells to anordrin, B T qPC re l t ld changes of s i levels of genes under regulation by the estrogen classic pathway (sue as BRCA1, ApoD, a), when CF ? ceils were treated with anordrin (AMD), tamoxifen AM) or raloxifene (RA , compared to -7 cells without drug treatment. Anordrin treatment d d not significantly affect CA t ns a tp n» hot tamoxifen treatment significantly inhibited transcription of S C and X7 r As. C, blot thai removal of t l o t culture edium of MCF-? cells in increased x s of ER 3 at tire protein level, visible in the expression levels of i ER I or Figure 14: Anordrin or analog thereof anordrin) Inhibits Heel a d Is k wa cell growth. Figure : 6µΜ ANO does not n the s level of integral 1 n both MCF-7 and A. MB~2 cells,. -7 cells were harvested and d A buffer. 4Gpg total protein of cellular ysate was used for Western blotting to determinate the expression level of tegr n Upper ge shows the expression level of integr t ; Bottom gel shows the amount of aetin. Figure 6 : ANO does not change food uptake significantly in all experimental groups under our testing conditions. A: ANO does not significantly n food n db/d mice; : AN does not significantly change food uptake compared with other groups ovar e tom ed (OVX) ice; C: AHO does not significantly cha ge uptake compared to tamoxifen (XAM) g ups in normal mice:. Figure 17: Total cholesterol n liver.. A: Total cholesterol in liver of ov tie to ed (OVX) B Total cholesterol in liver of M/AND group. Figure : Anordrin or analog thereof (such a anordrin) MC 7 culture d to have decreased p turnin yellow CF-7 cells were seeded into a 24 well plate at density of cells per wel containing drug at indicated concentrations n O Sa l medium for The pil of medium w s measured using a pH. meter. Figure IS: H d og ne I of anordiin is a dominant s r for iniubttmg cell proliferation. h ne s substituted by atk or al eny amine from. C2 t e i e derivatives of a ordio M A 2 cells are d to the d ug activity. Conee r ion dep nd n morphological and death of MP A 23i ell ; re The active drugs concentration ranges. Figure 20: does not bind to soluble - -36 Figure 2 1: Immunofluorescence staining ( eft of fi sections of l using tl o ese i iy labeled antibodies aga t E (top), E 1 (middle) E r (bottom). d were stained using DAM (blue). in the ght panels are corresponding bright-field images. Only d perinuclear localisation. Figure 22: A . n knockdown of R 3 specific iR A decreased migration o DA- B-23 cells, but transient knockdown of GPE (using specific si A) or control using scrambled si A resulted no significant effect on migration of M DA M 2 cells. Cell migration d matrixgel a . B, Western blot showing that specific si NAs were effective at down. E 36 id respectively a protein level. Figure 23 : knockdown © E 3 or GP E using specific siENAs decreased sensitivity of MCF ceils to both fe and aaordrin (or a ordri analogs) terms of f of the drugs glucose uptake m d cellular A levels,. A. Glucose uptake by M€F-?-cells treated with tamoxifen a ord n (AND) measured us g analog 2 8 G 2 7-n 2 no kd wn of ER- -3 or GPERI by specific s RNAs resulted " a significant decrease in glucose uptake tamoxifen TA ) or anordrk (AN } reated C 7 , as compared to drug-treated MCF-7 cells without Ai knockdown of ER 3o or GPER . . ATP concentrations in. CF-7 cells treated w h tamoxifen and/or anordrm (A ) were measured using fluorescence-based AT analysis k t. of ER o 3 or 6 E .I by specific s As resulted i a increase in AFT concentration in a o ife rea ed cells, bat a decrease anord n re ed cells, as compared with cells treated with corresponding: drug without NA knockdown, C Western blot showing effective knockdown o 36 or GPERI at the protein level by specific siRNAs. The present application provides methods d compositions for combination therapy comprising anordrin or analog thereof (such as nor r n) in conjunction with a second agent for treatment of cancer, reducing side f and reducing postmenopausal mptom( ) The inventions arc based on the discovery o the u ique properties and mechanism of actions of anordrin or thereof anordrin). After a large scale screening, we surprisingly found anord n or analog thereof ( anordrin) s a specifically selective estrogen receptor modulator of e b ne s ciat d esirog d proteins. On the other hand, anordrin or analog thereof as d bi s to G E l m d functions agonist on h GPE pathway, which m dn ates metabolic signals to balance the consumption of b e ergy. Th beneficial effects of anordrin or analog thereof (such anordrin) s include: ) the inhibition of malignant el migration and growth regulated fe o b a e-as ociated esrrogen r pto through estrogen ned d 1 R/V FE pathways it) the modulation of estrogen metabolic effect as an agonist which leads to reduction of po ¾ nopanaa sy pto s m f t liver, weight , high l d triglyceride, d osteoporosis and organ atrophy, ) the neut ralizat n of detrimental effects b drugs a raloxifene and ana ro which for osteoporosis, non-alcohol st ohepa i (NASH), atrophy of m d cancer the present invention in o e aspect provides methods for treating cancer comprising administering an nordr i or analog thereof (such as anordrin) alone or combination with at least one other agent selected fro the group consisting of tamoxifen., raloxifene or ctioaal equivalent thereof, and an aron ta e inhibitor. n another .aspect, there is provided a method of reducing side effect of at. least one other agent selected fro the group consisting of tan o fo n, raloxifene or functional equivalent thereof, an an aromatase inhibitor, by administering anordriit or analog thereof (such as anordrin) in combination with olher agent In another aspect, there provided me f of reducing a postmenopausal syndrome by administering an anordrin or analog thereof such as anordrin) alo e or in combination with at least otter agent, w ei n the other agent raloxifene or equivalent thereof n another sp , there is provided a method of reducing blood i oeit i thromboembolism by administering an anordrin or analog thereof (such anordrin) alone or in combination: with at least one other agent, w tei the other agent is raloxifene or functional equivalent thereof Also provided are pharmaceutical compositions comprising anordrin or analog thereof (such as anordrin) and at least one otter agent selected from group consisting of tamoxifen, raloxifene or functional equivalent thereof and an aro a ase inhibitor. t to fee understood by a person of ordinary skill the art that combination therapy methods described herein requires © agent or s be n in conjunction another age t conjunction with" to ad trai st of one treatment modality in addition to another treatment modality, suc as administration of a o in o analog thereof an rd i ) described herein in addition to ad it tration. of the seco d agen to the individual suc , conjunction with" fe to adminbnation of one modality e e d or after delivery of the other treatment modality to the individual. The methods described herein are generally useful for treatment of . As use herein, e is an approach for obtaining beneficial or desired clinical r . example, for treatment of cancer, benef ial or desired clinical results but are ot limited to, one or more of: alleviation of one or more , di inishn nt of extent of disease, preventing or delaying spread (e .g metastasis, for metastasis to long or to the lymph node) of disease, preventing or Maying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, and n (whether partial or total). Als encompassed by " e me is a reduction of pathological consequence of proliferative disease. The methods of the invention contemplate any one or more of these aspects of treatment Individuals having "triple negative breast cancer" se herein refer to individuals who clinically negative br expression of estrogen receptor (EE), progesterone receptors (PR) and E 2 protein. ¾ refers to e raae >o«nd estrogen receptor. facilitated onto plasma membrane through th paletitoylation modification at a Cysteine residue of ts estrogen binding domain (L . is a truncated E variant. It remains n mito lat t oti f (445-453) and possesses a unique 27 a ino acid instead of 14 n i region (456-595) of eng E - at C tern i s. Si ce E 36 possesses a partial LED and predominantly localises at m memferane and cy o o , it does not h n with estrogen resulting n losing the modulating ability of estrogen classical pathway. m positive/ Y GFR positive *' used herein refer to individuals who are clinically positive fo tnembrane-bonnd estrogen receptor, epidermal growth factor receptor E F or vascular epidermal growth factor receoptor (VE ), The term "effective an o r used herein refers o an a ount of a co pound or compositi on sufficient treat specified disorder, condition or disease such s ameliorate, palliate, lessen, and/or delay o or more of its symptoms n reference to cancers,. an effective a oun comprises an amount sufficient to cause a t mor to shrink and/or to decrease the growth rate of the tu or (such as to suppress tumor growth) or to prevent delay other unwanted ce l proliferation. The terra " dividual" d ng humans. An individual includes, but is limited to, , bovine, horse, feline, a or primate. some di s the individual is human. The pract ed ad vant setting. "A n * refers to a clinical setting in which an individual had of a particularly cancer, generally (bit not necessarily) s to therapy, which includes, but not i to surgery (such resection), radiotherapy, and chemotherapy. However, f their history of the proliferative disease (such cancer), individuals re at risk of development the disease Treatment ad n ni tTa io n the "'adjuvant setttng relets to a subsequent mode of The degree of risk (i.e., when individual in the adjuvant setting is considered "hig risk" or "low risk") nd upon several factors, most usually the en of her first treated. The hods provided herein practiced a "neoadjuvant setting 5' i.e., th method may be carried out before the pri aty/de i tiv therapy.. In some m n the individual s previously bee tr . In ii n the individual has not previously been treated. In the treatment k a first line therapy. s a linear or branched saturated rbo or example, an a ky! group can have to 2 carbon (i.e.. or 1 to 0 carbon atoms (i.e., (€ C alky!}), or to 8 carbon atoms (i.e., (C:rC ¾alk )}, or ! io 6 carbon (i.e., (Cr a! y )), or 1 to 4 carbon ato s (i.e. , C yl ), Examples of suitable kyl groups include, but are not limited to, methyl (Me, ~CI¾), ethyl (Et» € ! ¾ ), l-propyi ( Pr ^propyl, ¾ CH € H ) 2 pr pyl r /-propyl, - ¾C -butyl - , ty , C C , 2 t y -propyl u, /-butyl, € I C Cf¾)s 2 bu y . -b tyl - : 2 e t 2 r >T ( , /-butyl, ~ ), -pentyt penty , ¾ S , 2-pen 3 pe¾ yi (C C¾ ) } 2 t et yl 2 ui € (C C:- C }, 3-methyl-2-butyl Η - Ϊ , 3 r t y l- -butyl {-C C C (CH*) ), 2- e . l I- ~ C ¾ e y ¾ C 2 ex y1 (-C (C¾ ) sC C ), 3-hexy 1 ( C ( C }( C € ¾ ) , 2- e y1 -C C C 3-methy!~2-pentyl ( ¾CI-¾}C ( }C C ) 4 et yi 2 p yl (- (C }CH C (C¾ ), 3-met.h -3~penty (-C(C¾)(CE C1¾) , 2 ei yi 3 pe (~ (C rC ) C ¾ ) ), 2 et h: I 2 ty B B , 3 3- methy -2-b l C-CB(C¾)C(CI%} and oety C¾ ) ) . is a linear or branched hydrocarbon w t at least one carbon-carbon double bond Fo , a grou can have 2 2 earbo atoms ( e., -C or 2 t 10 carbon ( e . or 2 to 8 carbon atoms (i.e., or 2 to carbon atoms (l - or 2 to 4 atoms (l. ? a of suitable aikenyl s include, but are not l d to* ethylene or vinyl 5 (-C CH ) a yl -€ ¾ C. C¾ ) and 5-be eny -C¾ C C¾C¾CH^C¾). It is u d to that aspect of the invention described herein include n i and/or g l y of n n . Reference to " * a value or parameter includes (and describes) variations t at are directed to that value parameter per .For , description to "about X* includes 10 description of As used i a d in. the d singular for * , and include plural referents unless the context clearly lates otherwise, it i understood that aspects and variations of the i ve tion described herein include "consisting* and/or ''consisting essentially o aspects n variations. 1 s or cancer The present invention In aspect provides methods of treating cancer in an individual, comprising administering to the individual an effective of a dri n or analog thereof (such anordrin). so e i n , there provided method of treating cancer i an individual, comprising administering to the individual: a) an effective amount o aao dr n or analog thereof (such anordrin); and b) effective amount of at least one other agent selected from the group n i iing of raloxifene or functional equivalent and an a omatase inhibitor. so e embodiments, there is provided a method of treating cancer in an individual, comprising administering to the individual: a) an fe amount of anordrin or IS analog thereof {such as anordrin); and b an effective amount of raloxifene. n some embodiments, there is provided a method of treating cancer in individual, comprising administering to the individual: a) n effective amount of anordrin or analog thereof (such as anordrin); and b) an effective amount of tamoxifen. some e bodi ents there is provided a method of treating cancer in individual, comprising administering to the individual: a) effective amount of anordrin or analog thereof (such s ano rin); and ) an effective amount of lasofoxidene r e i e . In some embodiments, there is provided a method of treating cancer a individual comprising administering to the individual: a) an effective amount of anord n or analog thereof (such as anordrin); a b) n e e t e a oaft of an tro¾ol n some embodiments, the anordrin or analog thereof (such as anordrin) and the other agent are both administered orally. some embodiments, the a rdxm analog thereof (such as anordrin) a d the other agent are present i a single composition as the pharmaceutical ti for example n the form . oral dosage form. I ! embodiments, the cancer s selected from the group consisting of breast , l ng cancer ( s all cell lon a and n rnaii ceil Jung cancer), renal cancer, bladder cancer, pancreatic , cancer, prostate h r& cancer, colorectal cancer, k y h , and multiple myelom a rs embodiments, the individual is- mER positive n s embodiments, the individual is ECr R In embodiments^ the individual is V G embodiments, the id has solid tumor. In nt , there is provided a method of treating cancer n individual, comprising administering to the individual: a) an effective amount of anordrin or analog thereof (such anordrin); and b an effective ot t.of at least other agent, wherein the other ge t is an inhibitor. In some embodiments, there is provided a method of treating cancer art individual, comprising administering to the individual: a) an effective amount of anordrin or analog thereof as anordr ); and b) an f feet v amoun of a least: one other agent, wherein the other agent VEGFR inhibitor. n embodiments, there is provided a method of treating cancer n an individual, comprising administering to the individual: a) n effective amount of anordrin or analog thereof (such as anordrin); and b) an effective amount of at least two other agents, -wherein the other agent are an BGFR inhibitor and a V GFR inhibitor in some embodiments, the method further comprises administering to the individual another agent selected from the group consisting of tamoxifen, raloxifene o functional equivalent thereof, and an aroraatase inhibitor in some embodiments, the cancer s BGFR positive In some embodiments, the cancer is VEGFR positi ve In some embodiments the cancer is mE positive. In some embodiments, the cancer is BGFR positive VBGFR positive a embodiments, cancer is mER positive, GFR positive, and VEGFR positive. Suitable BGFR inhibitors include, for etu n a panit a erbtinib, e ni and vandet b Suitable VEGFR i bi or include, for example, b ci mab p opanib regor , and sorafenib. n some embodiments, the anordrin or analog thereof ( h as anordrin) and the other agent are administered sequentiall . In some embodiments, the anordrin or analog thereof (such as anordrin) d the other agent are administered simultaneously. so e embodiments, the anordrin or thereof (such as anordrin) and the other agent are administered concurrently. For example, in some embodiments, the administrations of the anordrin or analog thereof (such as anordrin) and the other agen are initiated at about the same (for p within m y o e of 1, , 3, 4, 6, 7 days). In o th administrations of the an rd n analog thereof as anordrin) a d the other agent are terminated at about the same time (for , within m y o of 2, 3, 4, 5, , or 7 In embodiments, the of other agent (for example for about m y one of 0 5, I, 2, , 4, . 6, , , 9, 0, I, or 12 months) after the termination of the ada nni t t on of the anordrin o er (such anordrin). la s d s the administration of the other agent initiated after (for after about any m of 0 5, 1, 2, 3 4, 5, 7, , 9, 0, , or 12 months) initiation of the administration of the anordrin or analog thereof (such as anordrin). n so e embodiments, the administrations of the anord n or analog thereof (such as anordrin) and the other age are initiated a d t i d about the same time la m embodiments, the administrations of th anordrin or analog thereof (such as anordrin) and other n are Initiated at about the same time and the administration of the other agent continues (for example for about any of 0 5, I, 2, 3, 4, 5, 6 7, 8, 9, 0, , or 12 months) after t r nat on of the administration of the anordrin o analog thereof (such as anordri n) some embodiments, the administration of the anordrin or analog thereof (such as aaordrin) and other agent stop at: about the sa e time d the administration of other agent is initiated! after (for example after about one of 0 5, l 2, 3, 4, 5, 7, 8, % , , or 2 months) the Initiation of the administration of the anordrin or analog thereof s h as anordrin). In so e embodiments, the administration of the anordrin or analog (such as asiordrin) and the other agen stop at about the same time and the administration of the anor ri n o analog thereof (such as anordrin) k initiated after (for example after about any one of 0.5, , 2, , 4, , 6, 7, 8, % , i , or 2 months) tire itiation of e administration of the other agent. The anordrin or analog thereof (such as aaordnn) and! other agents described herein can fee the age s e pharmaceutically acceptable sa s ereof and pharmaceutically acceptable esters thereof, as wel as ere somer nantio er racemic mixtures, and the like . The other agent or agents as described can e administered as well as a p a ma e al composition containing the ageni(s), wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier vehicle, or the like t he methods described herein administration of the anordrin and/or analog thereof (such as anordrin) and d e other agent in e ec ive amounts. n e bodi ents, an ef ect e is an amount sufficient to delay development. In embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. An effective amount can be administered in one or ore administrations n the ease of cancer, effective amount of the drug or composition ay; (i) the number of cancer cells; (it) reduce tumor (iii) inhibit, retard. s o to some preferably stop ca ce cel infiltration peripheral orpins; iv) inhibit (i.e., slow lo extent a d preferably stop) tumor (v) tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor, and/or (vi relieve to some extent o e or more of the symptoms t with the cancer. , there provided a method of inhibiting cell proliferation (such growth) m comprising administering to the i d a) effective amount a anordrin or a alog thereof (such anordrtn), and optionally b an effective amount of at l on other agent t from the gro n t of tamoxifen, raloxifene or functional e iva nt thereof and aromstase inhibitor. n some embodiment^ the effective amounts of the anordrit* or analog thereof (such anordrtn) n the other agent synerg ieally inhibit proliferation (such as tumor c ell growth) n embodim nts, at least about 0% (including for at least about any of 30% 40%, 60%, 0%, , or cel proliferation is inhibited. n s d , there provided a. method o tu or metastasis (such as metastasis of breast n , n metastasis or metastasis to the lymph node) in m Individual, comprising administering t the individual; a) a effective amount a anordrin or analog thereof (such as dri nd o ionall b m effective amount of at least n other agent selected from the group consisting of tamoxifen, raloxifene or n to al equivalent thereof, a d an aromatase inhibitor l t some s, the effective of the anordrit! or analog thereof (such as anordria) a d the other agent s ergist a ! inhibit tumo metastasis in. some embodiments, at leas about i % (including for example at. least about of 20%, 30%, 40%, 60%, 0%, 80%, 90% . or %) metastas is inhibited n some embodiments, method of inhibiting e stasis to lymph node is provided In o e embo iments method of inhibiting metastasis to the lung is provided.. In some embodiments there is provided a method of reducing incidence or burden of preexisting tumor metastasis (such pulmonary metastasis or metastasis to the lymph node) a individual, comprising administering to the individual: a) an effective amount an anordrin o analog thereof (such as no dri n) and optionally ) an effective amount of at least one other agent selected from the group consisting of tamoxifen, raloxifene or functional equivalent thereof and an ra ra a ase inhibitor. n e embodiments, there s provided a method of reducing tumor in an individual, comprising administering t the individual.:: a) an effective amount anord i or analog thereof {such as anordrin), and optionally b) an effective amount of at leas one other agent selected fr o the group consisting of tamoxifen, raloxifene o functional equivalent thereof and an aromatase h some th tumor s reduced t least about % (including for example at about any of 20%, 30%, 40% 60%, % 80% , or 0%). some b there is provided method of prolonging to disease progression of cancer n a individual, ri administering to the individual; a) an effe ct e amount anordrin or a alog thereof n h nordri ) and optionally b) an effective a ount of at least o other selected from be group i of n, i or k equivalent thereof, and an ar ata e inhibitor. n so e embodiments, the method prolongs the time to disease progression by at least any of , 2, , 5, , , , ¾ 10, l ! s or 1.2 weeks In some there is provided method of prolonging survival of an. individual having a pro fe rat e disease (such as cancer), comprising administering to the individual: a) effective amount an anord n or analog thereof (such as anordrin), and optionally b) an effective amount of least one other agent selected torn the group consisting of tamoxifen, raloxifene or functional equivalent thereof, and art aromatase inhibitor. In s n the method prolongs the survival of the individual by least any o 2, 3, 4, 5, 6, , , , 0, , 12, 1 or 24 In so e embodiments., the method is nsed to trea a primary tumor. In so e embodiments, a etl od of treating metastatic cancer (that s, cancer that has om the primary tumor) s provided some embodiments, the method is for the treatment of an advanced disease or a lesser ext ern of , h as low tumor burde In m odin nts mere is provided a method of treating ea cer at advanced stage. In some embodiments, the method is for the treatment of an early stag breast cancer. The methods may be ced in an adjuvant setting. methods provided herein ay also be practiced in a neoadjuvant setting, the method may be carried out before the primary/definitive therapy some embodiments, the method farther comp ses conducting individual following the completion of the treatment For example, some embodiments when the ca cer s breast cancer, breast conserving surgery or mastectomy cm be carried out within about 2, 3, 4, 5, 6, ?, S, , , or 12 weeks titer completion of the neoadjuvant chemotherapy, e embodiments the individual has previously been treated la some embodiments, the individual not previously been treated. n some embodiments, the treatment is a .first line therapy n some embodiments, the breast cancer has reo cu d after a remission. In some embodiments, the cancer is east cancer methods can be us ed. fo example, to treat, stabilize, prevent, and/or delay any type or stage of breast cancer, such as early stage breast cancer, non eta ta ie breast cancer, advanced breast cancer, stage IV breast cancer, locally advanced breast cancer, metastatic breast cancer, breast: meer i remission, breast cancer in n adjuvant setting, or breast i a neoadjuvant n I s embodiments, the method useful for preoperative systemic S ). some there of treating breast (which ay he 2 positive or negative), including, for , d breast stage I breast cancer, locally advanced breas t cancer, and metastatic breast cancer. In e bodi .e the breast cancer is type B breast ca In s e d , the breast cancer i basal cell breast cancer. n som , the individual diagnosed with T2, T3 or T4 lesion, or a stage , M O or Tl N!-3 MO. fa embodiments, the Individual has an EC performance status of ( ·· . embodiments, the individual has a to the ipsilateral breast som embodiments, the individual has undergone prior therapy (such a hormonal therapy) fa some embodiments, the individual has t undergone prior therapy (such as hormonal therapy) n embodiments, the individual i awaiting definitive surger In some embodiments, the cancer is resected cancer. s embodiments, the breast cancer is unreseeted breast cancer, su h as unresscted stage 1 or I breast cancer. n embodiments, the method is for treating n individual having one or of these risk factors resulting in higher probability of developing breast cancer than an individual without these risk fa t r s). These risk factors include, h t are no limited to, age, sex, race, diet, history of previous disease, presence- of precursor disease, genetic (i.e., hereditary) considerations, and i n ntai exposure. In s the individual may be who is genetically or otherwise predisposed to developing breast cancer who has or has not been diagnosed with breast cancer. Individuals at risk for breast cancer include, e.g., those having .relatives who have experienced this disease, and those whose ris is determined by analysis of genetic or biochemical markers. For example, the individual may be a human who has a . gene, genetic mutation, o polymorphism associated with breast cancer ( g . C , BRCA2, A , , RA S!, AR, I AS3 ER B2, and/or TPS ) or las one -o more extra copies of a gene (e,g , one or more extra copies of the E 2- gene) associated with breast cancer. n embodiments, the breast cancer ER2 negative, fa embodiments, the breast cancer is ER negative h some embodiments, the breast cancer is negative fa some n the breast cancer is ESP negative and ER negative. 1 some embodiments, the breast cancer is negative and E 2 negative n some embodiments, the breast cancer is ER negative and PR negative. In some embodiment, the breast cancer s ER negative, PR negative, and ER2 nefative. The methods described herein are also useful for treating other solid tumors (such as .advanced solid tumors). In some embodiments, there is provided a method of treating lung including, for non-small ce lung n (NSCLC, such as advanced SCL ), small cell lung cancer ( LC, such as SCLC), advanced solid te in the lung. In embodiments, there is provided a of treating any of ovarian cancer, head and neck cancer, gastric malignancies, melanoma (including metastatic melanoma and malignant melanoma), ovarian cancer colorectal cancer, and pancreatic cancer. In some n t method i useful for treating one or more of the following: cutaneous T cell lymphoma. TCL), leukemia, follicular ly p oma, odgkin lymphoma, and acute myeloid leukemia In some embodiments, the disease is a cancer of any one of the following: basal cell carcinoma, medulloblastoma, glioblastoma, multiple myeloma, chronic myelogenous leukemia (CML), acute myelogenous leukemia, pancreatic cancer, lung cancer (small c ell lung cancer and n-sma ! cell ung cancer), esophageal cancer, stomach cancer, biliary cancer, prostate cancer, liver cancer, hepatocellular cancer, gastrointestinal cancer, gastric cancer, and ovarian and bladder cancer. In some embodiments, the cancer s selected from the group consisting of pancreas ductal adenocarcinoma, colon adenocarcinoma, and ovary cystadenocafeinoma. n some n the cancer is pancreas ductal adenocarcinoma. In some embodiments, the cancer is a tumor that is poorly perfused and/or poorly i n some embodiments, the cancer s pancreatic cancer, including for example pancreatic adenocarcinoma, pancreatic adenos a ous carcinoma, pancreatic cell carcinoma, and pancreatic giant cell carcinoma. In some embodiments, the pancreatic cancer s exocrine pancreatic cancer. n some embodiments, the pancreatic cancer is endocrine pancreatic cancer (such as islet cell carcinoma). In some embodiments, the pancreatic cancer is advanced metastatic pancreatic cancer. Other examples of cancers that may be treated by the methods of the invention include, but are not limited to, adenocortieal ar i o a, agaogenie myeloid metaplasia, AJ S t d cancers (e.g., DS re a ed lymphoma), anal cancer, appendix cancer, astrocytoma (e.g., cerebellar and cerebral), basal cell carcinoma, bile duct cancer (e.g., r patk ), bladder cancer, bone cancer, (osteosarcoma and malignant fibrous ti tom ), brain tumor (e.g., glioma, brain stem g ioma cerebellar or cerebral a x cyto a (e.g., pilocytic astrocytoma, diffuse astrocytoma, anaplastic (malignant) astrocyioma), malignant glioma, ependymoma, oligodengltoma, meningioma, craniopharyngioma, haemangioblastomas, ed tilobiasto a s pr entori a primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, and glioblastoma), breast cancer, bronchial adenomas=¾arcinoids, carcinoid tumor (e.g., gastrointestinal carcinoid tumor), carcinoma of unknown primary, central nervous system lymphoma, cervical cancer, colon cancer, colorectal cancer, ron y o l fer i e disorders, endometrial cancer uterine ependymoma, esophageal cancer, Ewing's t y of tumors, (e.g., intraocular melanoma and retinoblastoma), gallbladder gastric (stomach) p t mi i a! carcinoid tumor, gastrointestinal tumor (GIST), germ c ll (e.g., extracranial, extragonad&l, ovarian), gestational trophoblastic tumor, head and neck a , hepatocellular (liver) (e.g., hepatic carcinoma e t ) ypophar nge cancer, let cell carcinoma (endocrine pancreas), laryngeal , laryngeal cancer, leukemia, o cavity ca cer, oral cancer, liver nc lung cancer (e, .s cell lung cancer, non-small cell lu g cancer, adenocarcinoma of m g, and squamous carcinoma of the lung), lymphoid (e.g., lymphoma) medulloblastonta, ovarian cancer, mesothelioma, metastatic squamous neck cancer, mouth cancer, multiple endocrine neoplasia syndrome, yelod splastic syndromes, : d dysp a tec pr l i¾raiiv i , nasal cavity and parabasal cancer, nasopharyngeal nei last m neuroendocrine cancer, oropharyngeal cancer, ovarian cancer (e .g , ovarian epithelial cancer, ovarian .ger cell i or, ovarian malignant potential tumor), pancreat cancer, parathyroid cancer, penile cancer, cancer of peritonea , pharyngeal cancer, phe chr cyto a, ineoblas oma and supmtentorial primitive ne roe t de ai. tumors, pituitary , u p imon ry blast a , , primary central nervous system lymphoma (microglioma), pulmonary ly phang omyo at sis, rectal cancer, renal cancer, renal pelvis and ureter cancer ( ran i al ce cancer), , salivary gland cancer, ski t cancer (e.g , non-melanoma (e.g., squamous cell carcinoma), melanoma, and M r l cell carcinoma), small intestine cancer, squamous e cancer, testicular cancer, throat cancer, thymoma a d thymic carcinoma, thyroid cancer, tuberous sclerosis, urethral cancer, vaginal cancer, vulvar cancer, Wilms' tu or, and p s rans ian ly p opr l ferative disorder (P D) abnormal vascular proliferation associated with phak t , edema (such as thai associated with brain tumors), and i syndrome. In embodiments, th cancer is a solid tumor (such as advanced solid tumor). Solid tumor includes, but is .not limited to, sarcomas and carcinomas such as fibrosarcoma, myxosarcoma, liposarcoma, cfeondw r a, osteogenic sarcoma, d a, angiosarcoma, endotheiiosarcoma, lympMngiosarcoma, lymphangioendotbeliosarcoma, sarcoma, soft tissue sarcoma, uterine sacronomasynovioma, mesothelioma, ' tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous c l carcinoma, basil cell carcinoma, adenocarcinoma, sweat gland c cinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bro ¾ ogen ar irto a, renal eel! carcinoma (including for example d clear ce cel carcinoma, papillar rena cell carcinoma, chromophobe renal ce l carcinoma, collecting due renal e c , .granular renal cell n d granular renal ceil carcinoma, re a ngio tyo ip as or spindle renal cell carcinoma ) hepatoma, bile i m m m&, rc n , e o , o , Wil tumor, cervical cancer, testicular tumor, lung carc inoma, eel! lung bladder , ept tal carcinoma, , astrocytoma, , craniopharyngioma, pin toma, e angio l on a, acoustic neuroma oligodendroglioma, enang a melanoma, a and retinoblastoma. In m embodiments the d neoplasm lymphoma) is a S-eell neoplasm. Examples of s s d «t e sot limited to, precursor B-cel! neoplasms precursor B- yra p b a i ken a pho a) and peripheral B e neoplasms - S l! hronic lymphocytic u ia pro!yt o i a/ lymphocytic lymphoma (small lymphocytic (SL) NHL), ly phop a tnac toid m i o , ma tel cell lymphoma, follicle center lymphoma, follicular cytologic grades: I (small cell), I (mixed small m large i) i l cell) anal/or srs y p : d redo i antiy small eel! low gra^fe/follictilar n lymphoma. (NHL), Intermediate grade f J ar HL, l ¾ « B~ceil lymphoma ( x ra da ie g MA T yp ~m y oid B cells) and/or Nodal ( g, on y o d B cells)}, p etsk marginal z lymphoma villous lymphocytes), Hairy cell ke pla eyro« /p a a cell myeloma t yel a a d multiple myeloma), f e lymphoma , primary mediastinal (thymic) B cell lymphoma), intermediate grade diffuse NHL, Bur s lymphoma, High-grade B- e lymphoma, Burkitt-!ike, high grade i n o a ik MHL, high ad lymphoblastic NHL, high grade small n n av d cell MfIL, bulky NHL, A S r ed lymphoma, and Waldenstrom's a rog iinen ). some m n the lymphoid neoplasm ( .g. lymphoma) a T and/or putative NIC-cell m Examples of T c d or putative e neoplasms include, but arc limited to, T el ( h l ly p oma le emia) and peripheral T- e r - li neoplasms ( vg , T eli lymphocytic e i emia prol mphocy k leukemia, and large granular lymphocyte leukemia (L T eil type a d/or -c ) cutaneous -cel! e g. mycosis go « Se¾ ry syndrome), primary T-cell lymphomas unspecified cytoiogkal categories , ~ cell, x d a d large cell), large cell, y p o pith oid cell subtype hepatosp e k d T-cell lymphoma, and subcutaneous panniculitic T-e lymphoma), ngioi nobla t T e i lymphoma. (A L angioe n r e lymphoma, intestinal T cell lymphoma . enteropathy adult ly p a ukemia (A t ), anaplastic e cell (A C ) ( g x €13304·, T- and nul -cell types), anaplastic large-cell and dgkirr s like). embodiments the lymphoid. neoplasm { g lymphoma.) is odgki s disease. For , the dg n s diseas may be lymphocyte predominance, d mixed celluiarity, lymphocyte ., and/or l mphoc t cb. I o embodiments, t cancer s in embodiments, h leukemia chrome leukemia. Examples of include, but are ot limited , chronic myelocytic- (granulocytic) leukemia^ chronic- y a d chronic lymphocytic leukemia (C ), n embodiments, the a s leukemia. Examples of a leukemia include, but are ot limited to, lymphoblastic leukemia (All,), te myeloid leukemia, acute lymphocytic leukemia, and acute myelocytic leukemia (e.g., yel ti , p ye oeyti , mye! m r ocytic, monocytic, and er thro e e a . I some embodiments, the cancer is liquid tumor o plasmacytoma. Plasmacytoma includes, but is not limited to, myeloma. Myeloma includes, but s not limited , an extramedullar^? plasmacytoma, a solitary myeloma, a d multiple myeloma. In some th is multiple myeloma. In. s e embodiments, th cancer is multiple myeloma. Examples of multiple myeloma include, but are not limited to, IgG multiple myeloma, IgA multiple myeloma, Ig multiple myeloma, IgH multiple myeloma, and nons ory multiple my lo . la some embodiment^ the multiple myeloma is Ig multiple myeloma In some embodiments, the multiple myeloma is IgA multiple myeloma la som embodiments, the multiple myeloma is a smoldering or indolent multiple myeloma n some embodiments, the multiple is progressive multi le myeloma. In some o multiple myeloma may be resistant to a dmg„ such , but no limited , h d xa e asoue (De xo b d a - and etp al ( R). n s embodiments, there are provided methods of reducing side effect of at least o e other agent by a ordr n or analog thereof such as a ord ) comprising administering to the individual an effective a ot n of anordrm or analog thereof (such anordrin) n combination with the other agent, wherein the other agent is selected from the group consisting of tamoxifen, raloxifene or functional equivalent thereof and an aromatase inhibitor. In some embodiments, the individual m R positive. In some e- dl em¾, the individual is EG positive. In some embodiments, the individual is V GF positive. Side effects of tamoxifen include, e.g., uterine cancer, nor ai o l steatohepatttis (NASH), cardiovascular and heart attack, diarrhea, nausea, headache, ho flashes, s us ti , h gain, leg cramps, and ankle swelling. Side effects of raloxifene , , decreasing blood triglyceride. cardiovascular and heart attack, Mood clots, s , d vein thrombosis, p l a y emboli s . effects of an s ole e.g., diarrhea. sea, headache. hot fl e , weight i , organ atrophy, d . n d s te is used basis for selecting for r treatment o reducing side effects of the other in n The levels of mER can be for example, for det n ing (and aiding assessment) in m y one or .more of the following: a) probably o likely sn bdi of an individual to initially receive treatment; b) probable or likely n n btli of an individual to initially receive treannentCs); c) responsiveness to treatment; d) probable or y suitability of an individual to continue to receive treatment; e> probable or likely uns itab ity of individual to receive treatments); f adjusting dosages; g predicting likelihood of clinical benefits. The present application encompasses any of these methods. or example, in embodiments, there is provided a method of treating cancer in an individual (such as a human ind idual) comprising administering to the individual: a) an effe ct e amount of anordrin or analog thereof (such anordrin); and optionally h) n effective a n of at least one other selected: the group consisting of tamoxifen, raloxifene or onal equivalent thereof, i ro t e inhibitor, wherein the individual hig level f m R. n so e embodiments, there is provided a method of treating cancer in an individual (such as a u individual) comprising administering to the individual : a) an effective amoun of anordrin or analog thereof stt as anordrin); and optionally b) a effective amount of at least one other agent selected f the group consisting of tamoxifen, raloxifene or functional equivalent thereof, and an ron a ase inhibitor, wherein the level of ER is d as a basis for selecting individual for treatment n , the individual selected for treatment if the indi vidual has a high level of n E . e embodiments, the level of mER is determined by i unohi toc em h'y method. In the level of the E is base protein expression level. In some embodiments the level of the ER is based on mRNA level, n some embodiments, the level of the mER is based on. Ca2 signal in response to estrogen stimulation. In some embodiments the method further comprises determining the level of the R prior the treatment n embodiments, the method farther comprises selecting the individual to treatment based on th level. The levels of mER be a high level or a low level as compared to a control sample. In embodiments, level of the mER in individual compared to the level of the in a control samp e In some embodiments the level of the in a subject compared to t e level of the . i multiple control samples. In bod nt multiple control used to a statistic that is used t classify t e e of E . rs an individual with can r- The classification or ranking of the £ level ( e , high or low) be determined relative to a statistical distribution of ro levels. embodiments, t classification or ranking s relative to a co trol sample obtained from the individual a embodiment the levels of the R is classified or relative t statistical distribution of control levels. In some embodiments, the level of the mER classifi ed or relative to the level from a r l s obtained from the subject Coatrol m s cart be obtained i the sources a d as n a eontrol samples. & some embodiments, the control is d from different individual (for example an individual ot having cancer and/or individual sharing similar t , a d identity)- In so e embodiments the sample tunvor tissue , the control pl may be a non-cancerous sample ro the s individual n s embodiments, multiple control samples (for example from individuals) are used to determine a range of levels of mER i a particular tissue * organ, or cell populati on n s embodiments the oontrol. l i cultured tissue or cell that beea determined to be a proper coatrol In entbodirnents, the control i a cell tha does not express n n so e embodiments, a clinically accepted normal level a standardized test is used as a control level for determining the mER level. k some embodiments, reference level of mER in the subject is classified as high, medium or low according to a scoring system, such as a n m no s c emist bas d scoring system. n so e embodiments, the mER level is determined by measuring the level of a mER in an individual and comparing to a control or reference e .g -, the edian level for the given patient population or level of a second individual). Fo example, if the level of mER for the single individual is determined to be above t e median level of the patient population, tha individual is determined to have high expression of t e mER. Altern atively. if tie level of m for t e single individual determined to be below d edian level of t e patient population, that individual i determined to have ow expression of t e n ER In m n , t e individual is compared to a second individual and/or a patient population which is responsive to treatment embodiments, the individual is compared to second individual and/or a patient population which is not responsive to treatment. In any of the embodiments herein, the level are determined by measuring the level of mER Far example, if the level of an n A encoding r E for th single individual is dete ti ne to be above the median level of the patient population, that individual is determined to have a . igh level of an R A encoding mER.. Alternatively, if the level E the E single i dividual is de r e l to be below the level of re patient t »d d al determined t have a low level of s« R A encoding ER n m embodiments, the reference level of E R is determined by ob† ing statistical dist b tion of mER In d , bi inf r at s methods used: for the determination d classification of the levels of mER, alternative i nfox nat approaches have been developed to e gene set expression p x fi e using gene expression profiling d . Methods include but are not limited to those described n Segal, E. a . Mat. Genet 34 :66 6 (2003); Segal, E. et ai. Mat. Genet 3 1090- 098 (2004); Barry, W . . e a . Bloln s 21: 1943-1949 (2005); Tia , L et al. l Acad i USA 02: 44- 49 (2065); Novak A and Jain A N . Bioinfor ati 22:233-41. (2006); Marietta et al. B k f r a ics 23 :2063 72 (2007); E u se ake i , MC io nfo i s 8 p 6 :S (2007). n embodiments, R A s determined, and a level is an m level less than about 1. , .2 i .3 : i.5, 1, 2, 2 2, 2,5, 2.7, 3, , 7, 0 ,. 20, 50, 70.. 00, 2 , 0 , 00 r less tha.it 1000 t at of w at is considered clinically ot to the level obtained from a I some embodiments level is an R .level than about 1.l s .1 .2, 1.3, .5, .7, 2, 2.2, 2.5, 2 3, 5, 7, 10, 20, 50,. 70, 00, 200, 500, 000 times or tha 000 tiroes to of wh t eo .det«d as in ai!y m or to the level obtained from a control. In some embodiments, protein level is determined, for example b i m«noh sto he is fy . For example, the criteria fo low or high levels he d based on the number of pos ve sta n g cells and o the intensity of he staining, fo by an antibody that specifically re og t e the protek. In embodiments, the level is low if le s n about %, %, 10% , . % 20%, 25%, 30%, 3 %, 40%, 45% or 30% cells have positive staining. n embodiments, the level s low if the staining is 1%, 5¾, 10%, %, 20%, 2 %, 30%, 35%, 4 %, 45%, or 50% less intense than positive control staining. In some embodiments, the level is high if ore than about 40%, 45%, 50%, 55%, 60%, 05%, 70%, 75%, 80%, 5% or 90%, cells positive ta g m i , the level is tti if the staining is as intense as positive control staining. n some embodiments, the level is high if the staining is 0 s 5% , or 90% a intense positive control staining. In embodiments, strong staining, moderate n , and weak staining are calibrated levels of staining, wherein: a range is established and the intensity of staining is binned within the range. n so e embodiments, strong sta ing above the 75th percentile of the intensity range, moderate staining s staining f the 25 h to the 75th percentile of the intensity r ge, and. low is staining below the 25th percentile of the intensify range. In one skilled in th art a d familiar fe a particular staining technique, adjusts the bin and defines the ste ng e ri In embodiments, estrogen sensitive level is te n , for example b Ca - oscillation or electrophysiological patn a p. For , the criteria tor low or h gh levels can be made on the n of C + concentration or signal of positive cells, for by using In the level is low less than about 1%, 5%, 0% %, 20 25%, 30%, 35%, 40 , 45%, o 50% cells positive sensitivity. In some embodiments, the level is low if the change of ¾ concentration or responsive signal is 5%, %, 5 20%, 25% , 35%, 40% 45%, or 50% less Intense than a positive control sensitivity. In embodiments, the level .high if ore than sh 40%, 45%, 50%, 55%, 60%, 65%, 70%, 5%, ¾0% 5¾ , or 90%, cells have positive change. some embodiments, the level is high if the sensitivity is as n as positive control sensitivity. In embodiments, the level is high f the ch n 0%, % or 90% as n positive control In some embodiments, sensitivity, moderate sensitivity, weak s nsit ity are calibrated levels of C$2* signal in cells, i a . n is established nd the intensity of * signal is binned within the range. In some embodiments, most sensitivity is the change of * signal above the 7 t percentile of the intensily range, moderate sensitivity is the n of signal the 25th to the 75th. pen em !e of the intensity range, and low se i s vity is the change of signal is measuring below the :25th peree le of the intensity range n some aspects one skilled in the a t, and familiar with a particular perfusion technique, adjusts the bin and defines the signal recording categories. Methods of reducing syndrome n di there are provided methods of reducing a postmenopausal symptom in an individual, comprising administering to the individual an effective a ount of an a ord n or n thereof (such as norf ri ). n some embodiments, there are provided methods of reducing a -postmenopausal symptom in an individual, comprising to the Individual: a) an effective amount of a anordrin o analog thereof (such as anordrin); and ) an effective amo n of at leas on other agent is selected from the group consisting of raloxifene or equivalent thereof and an aro atas inhibitor. n some embodiments, the anordrin or analog e (-such as anordrin) and the other agent are administered sequentially. In some embodiments, anordrin or analog thereof (such anord ) and the other age t are h n ane y (lor example m a single composition, such as t e s a ti ai compositions described herei n) Postmenopausal descri ed include, tot a not i to, fat e weight blood triglyceride and osteoporosis atrophy. for e i * s there is provided a method of prevetttiag fo reducing of) osteoporosis individual, o administering to the an effective amount of an an r ri n or og thereof (such as anordri ) n n there is provided a method of preventing (or reducing symptoms of) osteoporosis in an individual, comprising administering to the individual: a) an effective amount of art anordrin or analog thereof (such as anordrin); d b) an effective a of at least agent, wherein the other agen is raloxifene or functional thereof. In some embodiments, the other agent is raloxifene. In m embodiments, the her agent selected front the group consisting of tamoxifen, raloxifene lasof xit ne ba^edoxifene, ar x fene or eloxi e, pen ifene and levormeloxifetie. In me e odi ent , there is provided a method of preventing (or reduc g symptoms of) osteoporosis in an. individual, comprising administering to the individual; a) an effective amount of an rdr or analog thereof (such anordrin); and b) effective of at least one othe agent, wherein the other agent is n aro ata e inhibitor. In some embodiments, the other agent is ana tro o e In some embod ents, the method further comprises administering to the individual an. effective amount of calcium. Suitable amounts of calcium include, are not limited to, about to about 50 g da such as about 10 to about 2 mg/day, abou 50 to about 500 mg/day, In embodiments, the method further comprises administering to the individual an effective amount of vitamin 0 , Suitable amounts of vitamin D include, but are not limited , about 400 to about 80 da as about 500 to about 000 d y, I s e embodiments, there is provided a m t d of en (or redudiig symptoms of fatty liver in an individual, comprising administering to the individual an. effective amoun of an anordrin or analog thereof (such as anordrin). In some embodiments, there provided a of preventing (or reducing symptoms of fatty liver n an individual, comprising administering t the individual: a) effective amount of an anordrin f analog thereof (such anordrin); and b) m effective amount of at leas one other agent, wherein the other agent s raloxifene or functional equivalent thereof In some embodiments, the other agent is raloxifene. n some embodime s, the other agent is selected from th group consisting of tamoxifen, raloxifene, lasofo i e , ba¾edosifene, ar o i ene ©ra o , o pe ifene, and levormeloxifetie. In s embodiments, there is provided a method of preventing (or reducing symptoms of) fatty liver n an individual, comprising administering to the individual; a) an effective amount of an anordrin or thereof (such anordrin); and b) d c tive amou t of at least o agent, the other i an aro ata inhibitor. In some embodiments, the other age t is anastrazoie. some embodiments, there provided a method of preventing (or reducing symptoms of) insulin an individual, administering the individual effective amount o anordrin or analog thereof anordrin), in. n d there provided method of -preventing (or reducing: of) Insulin nc i an v pri administering to the individual: a) an effective amount of anordrin or analog thereof (such anordrin); ) effective o of at least oilier agent, wherein the other is raloxifene or -functional equivalent thereof so e embodiments, the other agent is raloxifene In some e bodiments, the other agent is selected from the grou consisting of mo raloxifene, la^foxitene, ba edox ene ra ifene o ne xi ne . s emifene and levo xifene. In so e e odimeats, there provided: method of preventing (or n of) insulin resistance in an individual, comprising ni ri I the individual: a) an effective amount of an anordrin or analog thereof such anordrin); and b) an effective amount of at least one other n wherein the other agent s an a nat s . In so e b , the other agent In. e is provided a of reducing sugar uptake or increasing cellular ATP concentrations or both in an individual, comprising administering to the individual an effective amount of an anordrin or analog thereof «eh a anordrin). I some m en s there s provided method of .reducing sugar uptake or increasing cellular ATP r or both in an individual, comprising is in to the individual: a) n effective a ount of an anordrin or analog thereof (such as anordrin); and b) an effective amount of at least one other agent, wherein the other agent Is raloxifene or functional equivalent thereof In embodiments, the other is raloxifene. som embodiments, the other agent is selected ron* the group consisting of tamoxifen, raloxifene, aso xifer baxedoxifene, r o ifene r e oxif ne, ospemifene, and levor ! if ne. In embodiments, there is provided method of reducing sugar uptake o increasing cellular ATP concentrations o both i an individual, comprising administering to the individual: a) an effective amount of an anordrin o analog thereof (such as anordrin); and i an effective amount of at least other agent, wherein the other is an ra iase hibitor. n embodiments, the other agent i aaastro¾o!e. In some embodiments ., there is provided a method of preventing (or reducing symptoms of) organ atrophy in an individual, comprising administering t individual effective amount of an anordrin or analog thereof (such as anordrin). In so e embodiments, is provided a method of preventing (or reducing symptoms of) organ atrophy In an individual, comprising to the a) effective of an or analog thereof (suc as anord r ) and b) m effective m of at least o e other agent, wherein the other agent raloxifene or functional equivalent thereof, I . d , the other agent is raloxifene n some embodiments, other agent is selected fr o th group consisting of raloxifene, Jasofoxlfene, ¾ d s an xifene o n e oxife ne, , and I or e ifene In s e embodiments, there provided method of e e ti (or s s of) organ atroph in an individual, comprising ad steri ng to the individual: a) effective amount of an & dri. or analog thereof (suc w d ) ) aft effective of at least out- other agent wherein th other i an ar ma ase inhibitor. In e embodiments, the other agent anastrozole. m embodiments, there is provided a method of preventing (or reducing of) weight g ai s an comprising administering to Individual art effective amount of an n rdrm or analog thereof as anordrin) In embodiments, there s provided a method of preventing (or reducing symptoms of) weight gain in an individual, comprising administering t the individual: a) n effective n of an anordrin or analog thereof (such s anordrin); and ) an effective amount of at leas one other agent, wherein the other agent is raloxifene or functional e thereof n some embodiments, other is e in o embodia e , the other agent is selected the group consisting of tamoxifen, raloxifene, lasofoxifene, baxedoxifene, x ora o ife nc, osp r if e, and levormeloxlfene. In some embodiments, there is provided a method of preventing (o reducing symptoms of) weight gain in an individual, composing administering t the individual: a) effective amount of an anordrin or analog thereof (such as anordrin); and b) an effective amount of at leas one other agent, wherein the other agent s a aromatase inhibitor. In. some embodiments, e other agent is anastrozole, embodiments, there is provided a method of reducing blood triglyceride in an individual, comprising administering to the individual effective amount of an anordrin or analog thereof (such a anordrin). n some embodiments, is provided method of reducing blood triglyceride in individual, administering to the individual: a) an effective amount of an anordrin or analog thereof (such as a io dri n) and ) an amount of at. least one other agent, wherein the other agent is raloxifene or functional equivalent thereof h some embodiments, the other agent is raloxifene. In some embodiments, the other agent is selected front the group consisting of tamoxifen, raloxifene, lasofoxifene ba do fene ar oxtfen , rme ox ne, ospeniifene, and vorn o fene so e embodiments, there is provided a method of reducing blood triglyceride in an individual, in an individual, comprising administering to the individual: a) an. effective amount of an anordrin or analog thereof (such as anordrin); and b) amount of at least o e other wherein t e age t is an ma e inhibitor. In some the other agent is ana t o . some embodiments, there is v method of reducing visco ii and/or thromboembolism individual comp sing administering to individual er¾tive of an a rd n or analog thereof as anordrin). In m there is provided method of reducing blood viscoeiiy and/or thrcmboem.bol.bm i a individual, ri ad iste r g to the individual: a) effective amount of anord n or thereof (swell b) effective amount of at least one other agent, wherein the other agent is raloxifene or functional e t thereof Irs e embodiments, the other agent is raloxifene. In e bodime ts, h other agent s s d from the group consisting of tamoxifen, raloxifene, a of ifene ba edoxife e ra orme oxi ene os e ifene, and bvornieloxifene. In some embodiments, there provided method of reducing bloo vi ocity and/or thromboembolism n a individual, in m individual comprising administering to the individual: a) an ef ect e amount of an anordrin or analog thereof (suc as anordrin); ¾nd b) an effective amount of at s one other agent, wherein the other e m aro at e inhibitor in some embodiments the other agent is astro ole of st n n the context of combination therapy, the composition comprising: anordrin or analog thereof (such as anordrin) a d the other agent be administered simultaneously (i.e., simultaneous administration) and/or sequentially (i.e., sequential administration). n some embodiments, the anordrin or analog thereof (such aa.ordri.it) and the other agent (including the agents described herein) are administered simultaneously. term e ad nis ra ion as used herein, means that the anordrin or analog thereof (mch anordrin} and the other agent are administered with a ti e separation of no more than about S n tt te(s), such as no more than about of 10, , or Whe the are administered simultaneously the anordrin or analog thereof (such as anordrin) and the other agent may be contained in the composition (e.g., a composition comprising both the anordrin or analo thereof (such as anordrin) and the other agent, for example the pharmaceutical composition comprised herein) or in separate compositions (e.g., the anordrin or analog thereof (such a anordrin) and the othe agent ar contained in separate compositions). In some embodiments, the anordrin or analog thereof (such as anordrin) a d the other agent are administered sequentially. The term "sequential administration" as used herein means that the drug m the anordrin or analog thereof (such as anordrin) and the other e are administered with a ti e separation of ore than about minutes, such as more than about any of 20, 30, 0, 50, 60 or more minutes Either the anordrin or o thereof (such an rdr n) or other agen fee te first The anordrin or analog thereof (such as an d in) and the other agent are contained in separate i which be contained in the same or i!Ye ent packages. In n , of the anordrm or thereof (such as anordrin) and the other agent are concurrent, . , the administration period of the anordrin or analog thereof (such as anordrin) and tha of the other agent overlap with eac other some the anordrin or analog thereof (such anordrin) is administered for at least one cycle (for example, at leas of 2, , or 4 cycles) prior to the administration of the other agent. In embodiments, the other agent is administered for at least any of one, two, three, or four weeks. I embodiments, the administrations of the anordrin or thereof (suc as anordrin) and the other agent are initiated at about the same time (for example, within any one of 2, 3, 4, 5, , or ? days). In embodiments, the administrations of the an rdri or analog thereof (such as anordrin) and the other agent are terminated at about th same (for example, within any one of s 2, , , S 6, or 7 days). In some embodiments, the administration of the other age t continues (for for about a y one of !, 2, 3, 4, 5, 6, 7, S, 9, , I I or months) after the termination of the administration of the anordrin or analog thereof as anordrin). In some embodiments, the administration of the other agent is initiated after (for after about any of ! 2 , , , , 6, 7, , 9, 0, , or we months) the initiation of the administration of the anordrin or analog thereof ( h as anordrin). n embodiments, the administrations of the anordrin or analog thereof (such as anordrin) and the other agent are initiated and terminated at about the same bine. In some embodiments, the administrati ons of the anordrin or analog thereof (such as anordrin) and the other agent are initiated at about the same ti and the ad inistration of the other n continues (for exa ple for about an one of i , 2, 3, , , 6, 7, % , , or 2 months) after the termination of the administration of the anordrin or analog thereof (such as anordrin). n some embodiments, the administration of the anordrin or analog thereof (such as anordrin) the other agent stop at about the same t nd the administration of the other agent is initiated after (for e after about m y on of I, , 3, 4, 5, , , , % , I, or we months) the initiation of the administration of the anordrin or analog thereof (such as anordrin), The dosing frequency of the anordrin or analog thereof (s ch as anordri fi ) and/or the other e may be adjusted over the course of the treatment, based n the judgment of the administering phys ian en administered separate , the anordrin or ana g thereof (such as anordrin) and the other agent can he administered at different dosing frequency or intervals . For example, the anordrm or thereof ( < as a rd n} & fee administered weekly, while another e be administered more or less frequently. Various n atioi s and devices for achieving a are known art Exemplary dosing rt er provided herein. The arsordrin or analog thereof as anordrin) the other agent n h administered ing the route administration or different routes of administration. x admi $tra i n r re .further provided h some b m (for both simultaneous and sequential ad i tr ti n X the anordrin or analog thereof (such rdr n) and the other agent administered predetermined ratio. For example, its e bodir en s, the ratio y weight of the anordrin or thereof (such as anordrin) and the other n is about I to . e , the weight ratio be between about 0.001 to 1 and about 00 to about , or between about 0 to about and KM) to about . In m embodiments, the ratio by weight of the anordrin or analog thereof as anordrin) and the oilier s less than about of 0: , 50: L 30: 10: , 9 : , 8: 7 :I, 6: 5 : , 4:! 3: , 2: and : n some embodiments, the ratio y weight of the anordri n or analog thereof such anordrin) and the other agent is more than about any of 1: 2: 3:1, 4: S J, 6: , .1. 9 :\ . 30: 50: !, 100:3 . Other mhos e contemplated. The doses required for the anordrin or analog thereof (such as ord n) and/or the other agent ma (but not necessarily) be lower than what is normally required whe each age t administered alone. , In so e e a subtherapeutic of the drug the anordrin or analog thereof (such as anordrin) and/or the other agent are administered "Subtherapeutic a o or "subtherapeutic eveP refer to n ra o u that is ess than therapeutic amount, that i ss than the amount normally used when the drug in the anordrin or analog thereof ttc as anordrin) and/or the other agent: t alone. The reduction may he reflected in terms of the amount administered at a given administration and/or the amount administered over gi en period of time (reduced frequency). n embodiments, enough other agen s administered so to allo reduction of th normal d of the anordrin or analog thereof (such as anordrin) required to effect the same degree of treatment by at least o of S%, 10% 2 % 30%, 50%, 60%, %, 80%, 90%, or more. In son: enough anordrin or analog thereof (such as anordrin) is administered so a to allow reduclion of th normal dose of the other agent required I effect the same degree of treatment by at least about any of 5% %, 20% .3 % 50% 70%, 80%, $0%, or more. e embodiments, the doses of both the anordrin or analog thereof (such as anordrin) and the other agent are .reduced as compared to the corresponding norma dose of each when administered alone. In so e embodiments, both the anordrin or analog thereof (such as anordrin) th other age t re at a subtherapeutic-, reduced, leve , dose of a o x n or analog thereof (such as as o d riu and or the other agent s substantially established maximum toxi close (MT . For example, the dose of the n drm or g thereof w aaardrin) the o lier agent than about 0%, 40%, 0 20% or 10% of the MID, I s embodiments, the dose of n rdr or analog thereof (suc as ord n) d or the dose of the agent s higher that* what is n when agent is d alone r in n the dose of the nord n o a log thereof (such as s rdr ) and/or the other agent I substantially higher than the established maximum toxic dose (MI D) r , the dose of the an rdr t or analog thereof (such a anordrin) a d/or the other agent is mo e n about 50%, 40% 30%, 2.0%, or 0% of the M D of the agent whe administered so e i the of a nord n or thereof (such as aoofdrin) (alone or in m with other is mettided any of the following range about O to about 0.5 mg, about 0,5 to about 5 mg, about- to about Ϊ 0 ng, about to about 5 mg, about: to about: 20 mg, about 20 to about 25 about 20 to about 50 , about 25 to about 50 m about 50 to about. 75 ng about 50 to about 0 mg, about 7 to abou 00 , about 0 to about rag, about 25 to about 0 rag, about 0 to about 175 , !?5 to about 200 , about 200 to about 225 g, about 255 about 250 mg, about 250 to about 300 mg, about 300 t about 350 mg, about 0 t© about 40 mg, about 400 to about 450 , or about 450 to 500 mg a di the amount of a nordri or analog thereof - as anordrin) (e.g., a unit dosage form) is in the range of about. 5 mg to about 5 0 mg, such as about. .rag to about 300 mg or about 5 mg to about 200 mg. I , the of the nordr or analog thereof (such as anot n alone or n combination with another age t includes at least about any of 0.0 mg/kg, 0 0 mg kg, 0 1 mg kg, 25 mg/kg, 0.5 mg/kg, 1 mg/kg, 2,5 mg kg, 3,5 mg kg 5 t g k 6.5 mg kg, 7,5 mg kg 10 mg kg, mg/kg or 20 mg/kg In embodiments, the amou t of the anordrm or analog thereof (such as anord n) (alone or in combination with another agent) s at least about any of 0 0 ! nig/kg/day, 0.05 nig/kg/day, 0. f«g/kg¾ay, 0 2 g/ g a 0.5 g kg day 1 rng/ g ay, 2.5 mg kg day, 3 5 mg/kg/day, 5 mg/kg/day 0 nig g/d y 7.5 mg/kg/day, 10 mg kg day, 1.5 g/kg day or 20 mg kg day . In some- embodiments, th amount of the other agent includes at least about any of 0 mg kg, 0.05 mg kg, 0 .1 mg/kg, 0.25 mg kg, 0.5 rrsg/kg, ! mg kg, 2.5 mg kg, 3 5 mg kg, 5 mg/kg, 6 5 mg kg, 7 5 , .1 mg kg., 5 mg kg or 20 mg kg . In some embodiments, the amount of the anord ri n or (such as anord n} (alone or combination another agent) includes at least o any of 0.01 g g day, 0 05 mg kg day, 0 . mg g day 0.25 g ay, 0 5 mg kg day 1 mg kg day, 2.5 n g/k day, 3 5 n g/k day 5 mg kg day, mg/kg/day, 7 mg kg day, g g d mg/kg/day 20 mg/kg/day. Exemplary frequencies for the anord or thereof (such (and for t other agent) include, but are not limited onee 2 weeks, every 3 weeks, once every 4 weeks, once every weeks, or o ce every weeks. In some embodiments, the composit n is e at least about any o , 2x, 3 , 4x , 5x 7 i.e., daily) e , or three times dally, two times daily. In o embodiments, the intervals between each administration les than about a y o 6 months, 3 1 month, days, days, 2 days, 10 days, days, 8 y , days, 6 days, 5 days, 4 days, 2 days, or I day. In some embodiments, the intervals between administration are mote than about any o month, 2 months, 3 , 4 months, 5 t , 6 months, &months, or 2 s In so e embodiments, there is break in the dosi g schedule. In some embodiments, the interval e each administration is no mor than about a w e , The administration of the anordrin or a alog thereof (such as anord n) (and for the other agent) can be x n over extended period of ti e, such as tr n about a n up to about seven years. In embodiments, the composition is administered over a period of at least about any of 2, 3, 4, 5, , 7, 8, 9, 0, ! !, 2 , 24, 0, 36, 4 , 6 , 72, or onths in some embodiments, the individual is treated for at least about any of o e, two, three, four, five, seven, eight, nine, of ten treatment cycles. The dosing fre uency of the other agent can be the same o different from that ot the anordrin or analog thereof (such as anordri n) Exemplary frequencies are provided above. The anordrm. or analog thereof (such n) (and he o lier agent) described herein can be administered to an i dividual {such as human) via various t s including, tor example, oral, intravenous, , intraperitoneal, i t p«lmonar inhalation, Int ave !ar, intramuscular, subcutaneous, intraocular, intrathecal., transniucosal, and transdermal I embodiments, sustained continuous formulation of the o .p itlo¾ t be used A combination of the administration configurations described herein can be The combination therap methods described herein may he performed alone or In conjunction with another therapy, such surgery, radiation, chemotherapy, immunotherapy, gene therapy, and th like. Additionally, a person having greater ris of developing the proliferative disease receive treatments to inhibit or and/or delay the development of the disease. As w be understood by those of ordinary skill in the art, the appropriate doses of other agents will be approximately those already employed clinical therapies wherein the other agent are administered alone or in with other agents . Variation dosage will likely occur d d the condition being treated. As described above, in so e embodiments, d e other agents y h administered at a reduced level. Compositions, hits, and medicines The invention also provides n (such as compositions), kits, and uni dosages useful tor methods described herein. Also provided are any use described whether in the te of use as a medicament and/or use for an f c r of medicament. The methods of th present application comprise a rn r stration of anordrin or analog thereof (such as anordrin). Suitab anordrin or analogs thereof r described in ore detail s below. The methods of the present application in aspects compri.se administration of raloxifene or functional equivalent thereof. "Functional equivalent thereof d herein refers t compounds that functions through the n as raloxifene. For functional equivalents of raloxifene include, but are not limited to, as oxi n ba ed xifene ar o ii e TO elo fe n , o pe i , and le nte ife e. ln another aspect, the method comprises administration of an aroraatase inhibitor. Aro at s inhibitor refers to class of agents that inhibit aromatase activity. Aro al s inhibitors have been used in the treatment of breast cancer and ovaria cancer in. postmenopausal women to reduce increase of estrogen conversion during cycle with external testosterone. Suitable a on at se inhibitors include* but are not limited to , ana tro ole fi id ) le ro¾o e (Fe ra), estane (Aromas a) voro¾ole v r) fo e an entaron), and t¾dro¾ole iti « further comprises a , which includes, but is no d to, corn oil The lipid be present for , in the of about 5 ( w) s embodiments, the pharmaceutical composition further comprises (such as casein) Protein (such a casein) be prese t, for , the of about 5 5 w/ ) embodiments, the ratio by weight of the a ordr or analog thereof (such as anordtin) d the agent its composition is about J to s e embodiments, the weigh ratio is between about 0.001 about d. about 00 to about I, or between about 0 . to about I a d 0 to about . In bodiro nts the ratio by weight of the anordr or analog thereof (such as anordiin) and other agent is ess than about an of 0: 50:1, 30;!, 10:1 9: , 7:1, 6:1 5:1, 4:1, 3:1 , 2: !, and 1: 1 In some the ratio by weight of the anordrin or analog thereof such as nordrin) and the other agent is more than about any of : : , : , 4 :1, : , ; , 7:1, 8 , 9:1, 30:1, 50:1, 100:1 . In embodiments, the weight rat of an rdr or analog thereof (such as mordrin) d the other agent in the composition is about :2 t about 20:3 (including for a about 10: to about : 0, or about : to about 15 The o some embodiments ay e in a unit dosage form (s ch oral unit dosage form). Suitable un t dosage forms include, but are not limited to, capsules, tablets, pills, eaplets, gels, liquids , suspensions, solutions, i , powders or other particulates, an so . In aspect, there are provided kits comprising auordrin or analog thereof (such as anordrin) and the other agent either in separate containers or in the same container. Kits of th invention include or more containers comprising an r n or analog thereof (such as ano r n (or unit dosage and/or articles of manufacture) a d r at least one other and in some embodiments, further comprise in iru io for use in accordance with of the methods described herein. The kit may further compr e description of selection an individual su le or treat en Instructions supplied in the kit of invention are typically written i.n ruct on on a label or package insert: (e.g., a paper sheet Included in the kit), hut machine-readable instructions (e.g., instructions carried on magnetic or optica! storage disk) are also acceptable. In some embodiments, the kit comprises a) an effective amount m anordrin or analog thereof (such as anordrirs), and b an effect e amount of at least one other agent selected fro the grou consisting of tamoxifen, or n ion l equivalent thereof, d an aro at as inhibitor. In some embodiments, the kit comprises: a) an effective amount an nord n or analog thereof (such anordrin), and b) an effect e amount of a least one other agent selected from the g up of i raloxifene or a equivalent thereof * d arornat s inhibitor and c) instructions for administering anordrin or analog thereof (such anordrin) mid th te r agents sl tane us y . sequentially, or concurrently for treatment of c cer (or r described herein). The anordrk or analog thereof s anordrin) and the other agents can he s in separate containers or a single container . It is understood the kit comprise one distinct composition or two or more compositions wherein o e composition comprises anordrin or analog thereof (such as anordrin) m d one composition comprises another agen The kits of the invention are n suitable packaging. Suitable packaging include, but is not limited i bottles, jars, flexible packaging (e.g., Mylar or plastic bags), and the like. Kits optionally provide additional components such as and interpretative information. The present application thus also provides articles of manufacture, which include vials (such as sealed vials) b es jars, flexible packaging, and the like. The instructions relating to the use of the anordrin or analog thereof (such as anordrin) generally include information as to d , dosing schedule, and route of a nii i tr ti n tor the intended treatment The comain.ee may e unit doses, bulk packages (e.g., u .ti dose packages) o sub-un doses. For , kits ay be provided that contain sufficient dosages of the anordrin or analog thereof (such as anordrin) (such as anordrin or analog thereof (such as anordrin)) as disclosed herein to provide effective treatment of an individual for a extended period, such as any of a week, 2 weeks. 3 weeks, 4 weeks, 6 weeks, weeks, 3 months, 4 months, months, 7 months, 8 months, 9 months, or more Kits may also i l multiple unit doses of the anordrin or analog thereof (such as anordrin) and pharmaceutical compositions and instructions for use and packaged in sufficient for storage d use m for e a p , hospital pharmacies and pharmacies. Anordrin and its analogs The presen application provides methods and ti comprising anordrin or its analogs. I some di h anordrin or analog therefore has the structure of For ula ) where is hydroxy! or 0 (€ 0 )R 5* wherein R is Cr al yl; R wherein R5 are independently hydrogen, C s or phenyl:; s hydroxyi or wherein C - a y ;; w er . and R axe ind p entl , C a or is Ct-C a ky or C -C a yt; R ~ is C a yl or Cr C ikeay or a na aii acceptable salt thereof. In s e n i fi er s, (I) (Is): some embodiments.. Formula (I) Formula ( b) ; (lb) In R wherein R is i Cr C fc l (e,g C alkyi, ¾ kyi a kyl or !k ) . In some embodiments, R such as k or C ¾a kyl. Irs some mbo itn t i some embodiments, R is ethyl. n some d ¾ R is .hydroxy!. in om embodiments., In i , R is ¾ , wherein a d E are i p d atly hydrogen, (e.g., C ky!, € aJkyJ, i yi. lky Cjalkyi, C .sa l . C¾ai ky Cn y or Cr C k yl ( . . C tk yi C lkeny! C. k i , n k a kenyl, C alk nyl C a keny € a1 e i, s , a ay , o a ke y!), or phenyl. In e s . R ¾ d R are ir d p id ritiy a k (e.g., € alky . € d k , a y! Cjalkyi alky!, C ai y C a ky !, a kyi C a ky or Chalky!), - . ., y , €¾alkenyl C.4alke»yS Csa € keny , C a kenyi, C a keny k , ealkeay , a fc eayi, or or phenyl. i - n some embodiments, R wherein a d e e de y hydrogen, ky c g . a ky t, Chalky!, k C a ky , C ky! C aiky C«alk k , C or « ¾ C k yJ , C a k r*y 1 C¾ !ke yi C fc a eny , € keay , C?aikem/I, al ny , in C aikyi (e.g . a k l, , ky , ,a ky ¾alk € a k i t a kyl ky . *a kyt, y n l, or a ke a n a ke sy C¾a keny C ta C a ryi or w or phenyl. In m embodiments, and are independently hydrogen, or « . * „ M n som embodiments, R * a independently I rogen or iy n embodiments, ¾ and are d I ts en odi∞ t and ¾ are ind de y or C : a kyi.. In embodiments, R * are Independently hydrogen or k ny m R2 and ≥ independently hydrogen, l or y In some o n and R re independently hydrogen or ¾ iky In some embodiments, * and > are ind p d « y hydrogen or In some embodiments, is and is C C ¾a kyls such as C -C l y C . CrC¾alkyi or . n some b dimen ¾ hydrogen and R¾ i € atk ny1, C a k nyi or C l . n embodiments, R4 is ( β n is C ky ».g ,, a ky C alky!, , or ky!). I» soroe embodiments, R is y , such as CrCsaikyi or CrC¾alkyL In embodiments, **is m hi embodiments, s ethyl In some e , hy r x . n . is , In , is ¾ , wherein are i. e e«de«t y y C a ky (e.g.., C alkyl C^ikyi, C aikyi . W , C a kv C alkyi C«alkyi ,a k C alkyl, C a ky or Crfkyl), k y , Csalkenyl, C alkenyl y Csalkenyl. C eny , C a ken C^lkenyl, C e» , C alk yl or ¾e or phenyl n R5 , wherein * and are independently hydrogen, C c g . C alkyl, ¾alkyL a y a yl, C a ky , k C a ky ky , C^alkyk C ky or C fcyl , ¾ y C a keny!, a keny to C a eny , k nyl, C¾ iik y i aik ny k € a ke yi, C a enyi, or n or phenyl. n d , , wherein R * nd independently hydrogen, € C a¾yl e g., a k l, a ky , a!k k a kyk a kyl, a kyk C iky , C iky or - a y ., C i nyl alkenyl C a yi a y , a kenyl or e i o phenyl and Independently hydrogen, (e.g., C ky € a kyk alky C lky € aiky , C lkyi a ky , alky , , C alky or Crf l) . . C a ken k C a keny C aikenyk C a e yk C aikeay C lkeny , ken , C a enyi, or ¾ or phenyl n o ne , R de d i hydrogen, , or C Cv al e yt. . * , * and are independently hydrogen i . In embodiments, and R independently y n or Cr ¾ lkeny ft b i en s, R R are independently hydrogen, ~C alkyk or C¾-C lke l a some d n , ¾ d R re independently hydrogen or In embodiments, R and * are independently or yl In some embodiments, n are independently hydrogen, ¾ k or Is s, and are independently e or ¾a In some embodiments, and R are independently hydrogen or « .. In embodiments, * hydrogen d ¾ C-r C a ky , suc as a kyl, C.rC alkyl, C| € ky k or C In so e embodiments, R s is hydrogen a d i y suc as , - ¾ k y or C» ¾aIkenyl n embodiments, R is C - ky (e.g., C a ky , C alky C¾ lky aiky , or C l y ). In embodiments-, C $ €saikyl, s C -C iky o Cr C- ky . n so e embodiments, & s methyl. n embodiments, Rft is ethyl in some e bod ents, R is C alkenyl, J eny , ¾al e yl, or C kenyi). n s e embodiments R is C a ky (e.g., C kyi C iky , C ky Cialkyl, C .a ky or C ¾aikyk or C -C a ky In , .R is a n is ethyl. n some s, R7 is C i . In some embodiments, R7 Cr ¾ ky . some embodiments* the may have any one or more of the following structural features. I and R a e m ty and a d R5 the same moiety a) R (C R wherein * C s C aikyi; R k c) R * is or wherein and ¾ are independently hydrogen, k (e.g., C or » - i Ce a kenyi) or phenyl; d) s is ¾ or ¾ ¾ ; where n a d re independently hydrogen, l (e.g., C C i yl or C yl) - l e (e.g., - e or - , or phenyl In o embodiments* the p d may have a y one or more of She following structural features. n embodiments, d are same moiety. a) R wherein R is b) 0 (€ )R wherein R . C C a k c and d R s In embodiments, the m one or snore of the following structural features. Its and R same moiety and are the m a) R 0 C wherein |-C a k 1; ) C )R wherein R c) or ; wherein R 2 and are independently hydrogen, y or phenyl; and d) R is , or ; wherein R * are independently hydrogen, y or phen yl n some embodiments, the compounds may have m y one or more of the to owing structural features, n some embodiments, and are s iety and d the same moiety. a) R s 0 (C )R wherein C aik I; b) R Is ~G(CO)R wherein R s s C C ai y l ) R2 is f ¾ wherein R * d *fe are en k ¾ » , or phenyl; d)R s wherei n R and R fe are independently hydrogen, .»- . a k n or phenyl In era b d rae , the compounds have m y one or of the t¾ owing structural features. n some embodiments, a d are the moiet . wherein * an ¾ are independently hydrogen, . . ~ ¾ ¾ Cr ta lk nyl b) s « , a e hydrogen, y (e.g.. C C y (e.g., or or c) R 5 i hydroxy!; and d) is hydroxy! n o the o nd y have any one or r of the following structural features. In some embodiments, a d R are the same moiet a) R wherein R ¾ R ¾ are independently hydrogen, , t y or phenyl; b R5 is , or ; wherein ¾ n * are independently hydrogen, C h or phenyl; e R is h roxy!; and d is hydroxy In some e i , the compounds have any one or more of the following structural tur n n n a e the moiet . wherein R3* and. ¾ independen enyl; wherein R 5 independently hydrogen, ¾ o phenyl; c) hydroxy!; and d) hydroxy!. in n the o have m y or of following structural features: a) ¾ $ € ~€ s, l l (e.g., t or ethyl); b) R is methyl or ethyl . In ariordrjn or thereof has the of Formula ( ), R " and are independently hydrogen, Cr € ¾alkyl, or phenyl; d Is C C$alkyI or C ai ay ; or a pharmaceutically acceptable salt thereof. In embodiments.,. d ( I ) Formula a : n. embodiments, Formula I ) Formula ( b): n embodiments, s n some embodiments, R5, wherein R and Independently hydrogen, C c g . C a ky &lky a y a yl, C aiky , fky , C ik alk l, ¾ a ky . C ky or C fcyl , C a kenyl, a keny n l, C a yl, n , C¾ i k n i aik ny C a i, or k y or phenyl. n fi « R Is R. a d R5 t d k e g ., C a!ky a! C,a!kyk j aikyl, a ky ky . C iky C yl* C kyi or € . i), k (e.g., e y <¾alk C . n C ito yi C*alkenvl M k yi. Cs Jkeny C a ke y!, ny Cnalkenyl, or o phenvl n m m embodiments, R i ¾ , wherein and n hydrogen^ (e.g., C a kyl C a kyk C ky s lkyi, C a kyi a ky C a ky , ky! or rf kyi} Ci y . , a kenyi C a en i C^aikenyJ, alke«yl C eny , C a k , C lke C a e i a n C a a , or C aikenvl or phenyl in some ent . is , w d ¾ n hy C - a k l (eg.. C lk l aiky . , C a yi, C a y !ky C * y C ¾alky Csaikyi, Ctalkyl, al yl, or C te C«a k «yl or phenyl. n * a d are independently hydrogen, or te n embodiments, d R are de e den or k I s and are independently hydrogen or hi embodiments and R ¾ are indepe t y hydrogen, In some d n R ¾ d R fe are independently hydrogen or n embodiments, R * ¾ are independently or e n R and are independently hydrogen, or - . » e . n Rr¾ R are independently hydrogen n some embodiments, and are mdependently hydrogen or ¾ n s © bod en ¾ is hydrogen ¾ad is l * fe as Cj-C.4alk.yl, some ¾ is hydrogen R¾' - such a l C aa n or - i in some e , is C aiky3(e.g., , C alkyk C al y!, C lkyl C - Jky , or C^lkyl). In so e embod me s, CrC*aikyk such as a or C C a ky in d ! et y In s ethyl 1» so e d to . or € alken . embodiments, the or therefore a structure of Formula (III), w ere ¾ Is .. or R wherein ami R a e r g ,. d y ¾ or a pharmaceutically acceptable salt thereof embodiments, Formula (III) (Ufa): In some embodiments (III) is Formula (Mb): In. e bod is ¾ some embodiments, R is R and R5 are indepe de y , C a ky or C¾aiky!) C 2 € ¾alkeayl (e.g., keny aJkeny l a keny , C 1ken l C-?alk y l, € afk y , C¾ eny l ¾ » or phenyl. n some- R5 wherein * and are independently hydrogen, C c g . C iky &ky a ky a yl, C aiky , y C aikyi ky . ¾a ky k C ky or C fcyl , ¾ y C a keny!, €¾aikenyL to C a eny , n , C¾ iik y i aik ny ke y , C a eny i, or y or phenyl. n d , R * nd independently hydrogen, € C a¾yl e g ., a k l, a kyl . a ky a ky a y a kyl, a ky y C lkyl k C ik i or - a y ., C a ny l alkenyl C a yi yi a kenyl or o phenyl n Independently hydrogen, (e.g., C a ky l € a k , alky Ctalkyl € aiky , sa kyi C alkyi a ky , C¾aJk , C alky or C rf l) (e.g., C a ken k C a keny C ikenyi € i eny , C a ke , C lkeny , € ke» n , C a enyi or ¾ or phenyl n , R a e de d i hydrogen, or C Cv alke yt. . * , * and are independently hydrogen or . In embodiments, and R are independently n or Cr ¾ alkeny ft embodiments, R are independently hydrogen, ~C alky or C¾-C lke la some d n , ¾ and R re independently hydrogen or ¾ . a In embodiments, R and * are independently hydrogen or l In some embodiments, n are independently hydrogen, ¾ or Is ts, a d are independently hydrogen or € r aik 1 I e embodiments, and R are independently hy drogen « .. in embodiments, * hydrogen d ¾ a such as CrC alkyl C.rC alkyl, C -C or In so e embodiments, R s is hydrogen a»d i yl such as , C -C¾a k ? k C¾ k n or C » ¾ Ikeny n embodiments, the aaordrtn or analog thereof the structure of formula (IV), wherein is C or or pharmaceutically aceepttbie salt thereof. In some embodime ts. formula ( V) Formula ( Va : embodiments, (IV) Formula ( Va): n , ' 3s a e.g , C & y , !kyl, ¾ l y l i, C or ¾alky 1) Ir some is C r !kyl, s as C - ¾ iky! or - alky . ethyl n $ i t$, s ethyl. In some b o i ¾ ri s E is C-2-C«aitoyi . C alk w l, alk nyl *a fc ny C ¾lk y or C alk n ) . In s ra i , a o or analog ereof s at ord im rs some e d e the a ord r or analog thereof is a .compound having a structure depicted below. Those skilled in will recognize that s within scope and spirit of this invention. The invention will now be d ri d in te detail reference to the following o i t n examples. The foi © examples or her illustrate the invention but, of s , should not be d m y way limiti ts e EXAMPLES Example 1, Two e$troget di g te S m d SS, with respect to the rate of r ii e were reported in uterine to oi by Me ta e ( . Anordioi, the nest r ed and active metabolite of drin or analog thereof (such anordrin) was found to preferentially bind the 8$ with n affinity of ro te y 2x C In found to bi d both n n l . The selective binding of anordrin or analog thereof (such as anordr n with only one of tie estrogen - nd uterine eytosolie complexes suggests that anordrin or a alog thereof (such a a to drin m modulate specific biological f n tio s regulated by n There are currently two o t modulated by estrogen to regulate p l e biological functions. We first tested whether anordrin or analog thereof (such anord n) wa involved in t e classical of estrogen The E E X liga d i domain pr s ed GST sion protei {GST~ER- 4.80) B. oli a d purified ghitathlone . The binding affinities of anordrfo or thereof as ano.rd nX tamoxifen and 2 to the - LED g a E2 competition assay. It was found that SCn anordria or a alog (such as at could not the binding of 5 » 3 E2 to ¾ ¾ GST-EE- n the concentration of either fe or E2 blocked over 60 of 3 -E2 blading to L D (Figure A) Based these results we postulated that anordrin or analog thereof (such a or ria ) is volved g ating gene re s through the classical pathway of estrogen n B i is a key member of the anti apopt family of proteins. Its overe press n has been linked to kinds of cancers In humans. The -2 promoter contains an ERE sequence, and 2 A e io in MCF 7 cells has been found to be positively regulated E2 and by (19). n agreement with h s resul ts w e d the level of Bel 2 protein was enhanced by estrogen (Figure Lane and 4), and 7 5µΜ n was fo to b Bel 2 expression (Figure C, lane 2) In contrast, the expression leve either e -2 R A (data not show ) or protein (F re CS Lane 3) was not affected in M F- cells treated with ?,5pM nord n or analog thereof as no dri tt) Neither tamoxifen nor anordrin or analog thereof (such as anordrin) were found to affec Bel-2 protein expression in ceils cultured in medium using charcoal-stripped FBS in phenol red fr DM medium (Figure IC lane and 6, respectively) The expression of R A m R A als been d to he under the control of e in MCF-7 cells (20) We further demonstrated tha a ord n or analog thereof (snch as anordtin) did not significantly affect the xnR A level of B CA as measured using RT R C cells, while tamoxifen i ifi canti the synthesis of n A under the conditions (Figure MB 2 and 4) These results further support that an rdr or analog thereof (such as anor u is not Involved in the classic pathway of estrogen regulation. Interestingly while nor r or analog thereof (such as anordrin) did not appear to modulate ge e transcription thro ugh classic BR pathways, we slid ind that .5µΜ anordrm was ab e to inhibit :CF 7 el! growth b n or than 50% (Figure , column , ro 2) Furthermore, treatment of T4 D cells with 7$ anordrin or analog thereof (such as anordrm) not only blocked the increase in ce growth induced by ng tn EOF, but resulted in a further decrease below basal levels (Figure 6) Insulin ( ) binds to insulin receptor ( ) stimulating the phosphorylation of insulin receptor substrate (IRS) through the insulin like growth factor receptor ( FR ) pathway ospho lated IRS interacts with estr ge - R complex, which can then translocate Into the nucleus to regulate R A transcription through the estrogen classical pathway. The proliferation of MCF-7 cells is modulated by IL and th sensitivity of these cells to tamoxifen was fou d t be increased after I r f om culture 21) or when IRS was transiently knocked down R S speei e A (22). the L i S G l BR pathway plays an important r e the regulation of MCF-7 proliferation. Interruption of the S G l E pathway should to the proliferation of MCF-7 cells i more dependent o MIES. Consequently, the n of MCF-7 cells with disruption in the pathway would b decreased, while the e to modulators of MIES would be s To test thi hypothesis we i duced MCF-7 ce ls - ree ediu for two Drug sensitivity of ce l growth was tested by n i the cell after 4h of in l iio (Fig The te on IC50 of MCF-7 cell growth d t that enhances the sensitivity of MCF-7 cells to ta oxife « while e r s t g the sensitivity to anordrin or analog thereof (such anordrin) (ooltttna ) Moreover, the presence of 2G M anordrin i the culture medium did not affect the .ability of tamoxifen t iahibit MCF-7 cell growth (eol n row ! v r 4). As s of ER 36 MCF-7 cells Increased response to l of lin from the culture i the expression levels of G E n R 6 did change (F g. DC). These results further illustrate that the activity of anordrin s independent of the classical pathway. Furthermore, they suggest tha anordrin may inhibit MCF-7 cell growth ti of the MIES pathway, especially such as ER o 36 pathway. Ss effect their regulation of ceil proliferation, migration, cell-cell junction and and energy in taho rn through series of scaffold protein complexes, ER- association with the plasma membrane is facilitated by p mito tion at. residue C447 in the LED. ER- -36 is truncated R variant, retair g di palmltoylation motif (44S-453) and possessing a unique C ter i a 27 amirto a d sequence n place of t e typical 0 amino acids (456-59 of ful ngth ER (1 . Since - -36 possesses a partial. L D and predominantly localizes to plasma membrane and cyto l, it may impaired estrogen binding, resulting in loss of the modulating ability of the estrogen classical ay To verify this, w measured the binding affinity of 3f E2 with T-E - a - purified from £ The results indicate that GST-ER- a -36 expressed from i does not bind to I-E2 (Figure 20). n contrast, S-E2 does hind to GST-ER- a -46, which has full length ER- - S We ne t confirmed thai E l - -36 re in H 29 cel hinds t 3 2 wit a similar a ity ( d nM) as found by ang ¾ data not s n . Interestingly, anordrin displayed a iphasic effect on 3H-E2 d to ER- -36, blocking 3 -E2 binding to ER- - at low concentrations and facilitating binding at higher concentrations (Figure 2A). Taken together, our data n light of the published studi es o SR.- -36 suggest that t may be exclusively volved in the M IB proceeded to a of ER.-o.-3S to study the physiological consequences MIBS modulation by E2 d SERMs a and highly expressed E o in A- -23 and . cel s d was o regulate ce pr feratiot*through the of MAP R ( 1/2 5 (23), We examined the sensitivity o DA B 2 anor r in terms of eel! growth. Ou cel results indicate that µ anordrin inhibits D A. -2 eel growth gn carnly while tamoxifen n has no effect (Figure 2 ) Anord n treatment s also found to Inhibit the proliferation of both e l A ika a.cells at ranging fi s M (Figure H A ). Additionally, anordrin of epG2 cells d inhibition of cell growth h cte ¾ d by biphasic dose n , with intermediate concentrations around 7 showing the greatest degree of inhibition (Figure 7A Phosphorylation of in He»G2 ce ls showed similar c dose response to anordrin treatment, with axi al phosphorylation occurring a concentration of µΜ anordrin (Figure 7 ) suggesting anordrin ac through E pathway to mediate its inhibitory effects on ce growth. Based on our findings we predict 5 a route of action throug MIES and propose a useful application for anordrin in combination therapy to abrogate the side Induced by traditional estrogen blocking treatments. E2-ER complexes associated with the . can modulate the biological functions of scaffolding proteins, snob as Cas-ass afed substrate ( as), also known as breast cancer a strogen resistance A 1) in humans. The l eg n p € a complex plays a fundamental role n the regulation of extracellular .matrix ( CM od cancer cell migra on and invasion. has previously been shown to modulate M M 23 ϊ c l migration (24), As anordrin has n reported as an ant -angiogenic agent resulting In inhibition of ce l migration and invasion ( 6 % we studied its ability to modulate MDA-MB-2 cel migration using niatiixgef 5 MDA MB 2 cells were exposed to either nM E2 or I ng ml EGF combination with anordrin or vehicle control In wells,. After 20 migrated cells were stained and quantified si plate reader at We found that both E2 and EGF slightly enhanced MDA-MB-231 cell migration 6 M anor a significantly inhibited migration of MDA-MB-231 ce ls in mediu containing either E2 or EGF (Figure 2E and F). interestingly, 0 anordrin more efficiently inhibited MDA-MB-231 cel migration m diated by EGF than by E2. Furthermore, we knocked down ER- 36 or G ER! n MDA-MB-231 ceils using specific siR As We found thai the migration efficiency of MDA M 23 cells e s d in response to ER o 3 to wr . contrast, ie eel! migration i eney was not affected when expression of G was knocked in M A M B2 cells (Fig. 22). ntegr translocation to the cell surface is regulated fe ie l Cas scaffold protein complex to l fundamental role In cell d migration egr n 3β ί has bee reported to be involved n MCF-7 ce l attachment as well as A-M 2 el! migration (25, 26).. Our results s ro e for anord n as a possible down-regulator o nteg n distribution onto the cell m n through negative od te of the E2 ¾ a i g n signaling T verif the hypothesis, we treated MCF- and M A B 23 cells 6 Μ anor n for hours m i measured cell surface t g n p distribution a F X -t be d ant nfeg i n.p antibody We found that anordrin down-regulated integrin j 1 distribution to the of MCF-7 (Figure 2 ) and DA-MB-2 (Figure 2G cells However, it d d ot affect the expression level of Integra either F-7 or -Μ -2 cells (Figure IS}.. Take together, we conclude that anordrin or analog thereof sueh as anordrin) binds to membrane-associated BR to inhibit cell migration a d e . Estrogen plays important role the control of y balance n fet a e . Estrogen modulation of metabolic signaling affects the central nervous system, liver, skeletal muscle, one, kidney, the cardiovascular y The co plex of estrogen and ts receptor cross-talks with Insulin (lL) i s in receptor ( ) or l plin/neur peptide Y ( Y) and their receptors to regulate food glucose t adipocyte composition. While studying the effects of anordr n and on MCF-7 cell growth, we observed that the media of cells treated with anordrin was ore yellow, indicating decreased pH (Figure S) One cause or th would be enhanced glucose n n In aaordrin-treafed cells compared to those treated with tamoxifen, To determine whether l ls was the ease we treated MCF-7 cells with different concentrations of either anordrin or t for 0 hours. The glucose concentration n the culture medium was measured using glucose assay kit Figure 3A shows that the glucose eone un¾ ion of media fr m - te cells was lower compared medium o cells treated with tamoxifen. We tested whether ano r could increase glucose metabolism n s oxifen-tr at d cells. 2x\ 4 MCF-7 cells r well in Ο Ι medium ontai g µΜ ta oxife and 0(¾ anordrin were seeded into 6 welJ plates. Glucose concentration in the medium was measured after hours. Figure 3 shows thai 0nM anordrin not only reversed the Inhibitory eff ec of p tamoxifen on glucose metabolism b further enhanced glucose consumption compared to control (Figure 4 , bar 1AM ¾ bar T A - n a mouse model of ep n resistance (db/ b E2 ha beers shown to increase energy expenditure, leading to reduced body weight (28 . We administered anordrin (suspended in 2 δµ1 sterile water containing 2.5% cellulose) d i at a dose of .45 g g body mass to db/db mice a d measured whole blood glucose weekly for 4 weeks using a glucose as kit The s show improved glucose consumption in d ¾ female m ce (grou 1) d to controls (gr 2) (Figure 3C) Food intake and body did ot significantly during the testing period (Figure Ϊ 6Α) Interestingly, rd in had affect o glucose in . d /d ice (data not shown). Estrogen is of the key a l o ne involved in the regulat n of glucose metabolism, od u g the balance between AT synthesis and ep i n offer adipose tissue. Decreasing e levels lead to increased fat storage and obesity in postmenopausal increasing the incidence of diabetes non-alcohol a o at (NASH). Consequently, n therapies, such fe c the incidence o SH in breast cancer patients. Our .e have d w tha aaordrin n n glucose metabolism in M F ? and db/db mice and we predicted that it could prevent Increased liver fa in ov ecto ed 0 VX) mice well as MASH Induced by tamoxifen in norma! m e . To test this hypothesis, the o 6 week ol mice were surgically excised. 3 days post surgery, the i e were .given intragastric inj ection of ri ne, E , a sd or vehicle control. Body mass food intake were measured weekly. We found that after weeks body increased in t vone and control groups, but re ai ed unchanged n 1 2 and an i n g ups (Figure 4A), Food intake was not. affecte n any of the groups ( igure indicating the differences were due to changes energy M ce were then sacrificed :30 $ g of liver, and total lipid was extracted using a 1ml of h o for : e ha ol (2: ) and 0 5ml physiological salt solut ion. Total cholesterol (TC) and triglyceride (TG) levels in the organic phase were measured using TC and TG assay kits (29). The results show decreased of TC and TG In the livers of ovari rn ed ( VX mice .for the anord n and E2 groups compared to controls but no change for the ri avone group (Figure 4D, Figure The paraffin sections of livers from the anordrin d E2 groups exhibited smaller fat deposits compared t t h se from the control and ipritlavone groups (Figure 4C). To further study the effects of an drin tamoxifen on s metabolism, normal 6-week old mice wer treated with either drug alone or in combination. Mice fed with tamoxifen at a dose of 4 5 g g body per day for 9 weeks showed a Increase in body mass (Figure ) and had increased indicators of NASH syndrome (such as TG deposition in the perinucleus) ar d liver TC levels compared t control m e (Figure 4 E d F ) Body weight, NASH syndrome and liver TG pheno y es were completely reversed in mice fed w h tamoxifen as above in combination with anofdrin at dose of 5 g g body (Figure 4, s £ and F). Liver T levels w re not different between any of the groups (Figure I?B We also found that a o dri n can reverse the increased ser m viscosity d TC levels induced: by tamoxifen treatment (Figure 5). Furthermore, i otl o nee (IF) staining of f s of e d against GP R l , ER m d E R f respectively showed that only GPERl localised at the pe cle compared to other receptors (ER- m d E S Fig 2 1) Takes together, the results that tamoxifen y induce NASH through inhibiting the function of GPER In contrast, nord n or analog thereof ch aor rirt) ts m of GPE Elevated TG deposition; in the n l may be caused y increased glucose uptake or a d cellular ATP concentration. Therefore, tested whether tamoxifen and a rdri or analog here f such anordrin) can regulate glucose uptake and cellular ATF through r GPERl Glucose uptake was measured using uore en J labeled glucose 2- B GX and ATP concentrations were d using AT analysis kit We found that anordrin enhanced 2 N DG uptake and cellular ATP w n ti t (Fig. 23 A and B , f enhanced 2 D uptake, but decreased cellular ATP concentrations Fig. 2 A and 8 ) Combination of anordrin tamoxifen did not change the 2 G uptake level m MCF- cells as compared to control with no drag treatment (Fig 2 ) This result indicates that anordrin o analog thereof (such anordrin) and tamoxifen regulate glueose uptake through inverse mechanisms. When ER o C PER was knocked down individually b specific siRNAs in MCF-7 cells (Fig 2 C. we found that the effects of each drog O 2 N DG uptake and cellular ATP concentrations were reduced (Fig. A and B) These results suggest that tamoxifen and anord n or analog thereof (such as anordrin) regulate glucose uptake and cellular ATP eoneer trat on$ through th erosstal between ER-a and G E . Aaoxd or a alog ihereof (such as ano d t ) also potential therapeutic benefits in the treatment of t p a , t was found to v t uterine atrophy in ovariect n e mice (Figure SB), and to decrease the n of tamoxifen-induced uterine and vaginal atrophy (Figure A and ) n particular, a corn oil and casein formulation of anordrin enhanced its activity to prevent uterine atrophy n ce as compared to a formulation using methyl-cellulose {Figure ), Importantly, while a rd n causes hypertrophy of endometrial epithelial ceils it does not induce endometrial epithelial cell proliferation with the epithelium remaining a monolayer, as compared to tamoxifen and 2, which both induce proliferation and development of a po!y a er (Figure A and € ) Combination treatment with anordrin a d tamoxifen resulted neither hypertrophy nor increased proliferation (Figure A). Osteoporosis i a progressive hone disease common in postmenopausal women, characterize! by decreased bone rua s and density. Decreased Ca"" concentration [C a"" } an Increased phoaphafe concentration ]) are clinical diagnostic markers d to Indicate progression of s Anordrin was f nd to prevent osteoporosis in ovari ect o zed indicated by increased seru (Figure I J A) decreased (Figure- 1IB), and increased bone density (Figure 1 0 a d E). t also found to decrease marrow cells l C . Estrogen, tamoxifen a d raloxifene all bind to LED of ERs to modulate the n classical pathway. Estrogen replacement hen py or treatment witli or raloxifene of po component of E l r .3Bs potentially leading to blood clot formation. We h t at a SERM th does not modulate the classical pathway of estrogen would not cause blood ots or ra M e large scale n, a o d n was identified as a compound inat doe not modulate E classical pathway, and also decreases serum viscosity induced by tamoxifen. We t¾«nd that the methyl group i of rdrin i essential decreasing anordrin binding affinity to E -L compared with in ir n (Figure! A, dinordrin vs «dria). Therefor, alky! or al en in 6 of anordrin is necessary for prevention of blood clots thromboembolism Tamoxifen a useful therapeutic as .antagonist of the ER l pathway, but also an agonist of .ERs inducing the proliferation f endometrial epithelial cells. Anordrin can neutralise a xifea ind ed proliferati on of endometrial epithelial ceils, and as is useful combination therapy. Based on our .findings, we d that anor&ria is an antagonist of R. Aaordfin does modulate the ER classical pathway it cm enhance estrogen metabolic signaling. We propose that n dri n is agonist of G ER through which it modulates estrogen metabolic signaling, n contrast, tamoxifen is an antagonist of GF a d inhibits estrogen metaboli c signaling . Discussion Estrogen binding to its mea brane as ciated receptors lead to yto ll € a * oscillations conveying l to the ra lu r matrix ECM) impacting cell migration.. i ¾R is se of the major Ca i channels involved in the regulation of diverse signal transd uction pathways. It been reported to tak part in the estrogen modulation of Ca release m endoplasmic reticulum 00), and also been shown to be involved i functional regulation of t n (31). o v the detailed molecular mechanisms underlying this action are not clearly understood. ER complex has been re e to regu te ce migration through c-Src (32). e~Sr is a non-receptor tyrosine kinase that plays an important r e in the regulation of cell adhesion, i i growth and differentiation. The key regulatory mechanisms of c-Src t rosin kinase involve the control of ts phosphorylation states and kinase activity, which n be modulated by *' signaling induced by 2 interaction with E . The c Sre- Ai (focal adhesion na e) C scaffold reacts w th focal adhesion complexes to regulate the aetin. y elet n. resulting m the modulation of cell motility 4 The complex interacts with i g n to regulate BCM md . Anordrin to membrane-associated BR blocks the of estrogen-mediated integrin translocation, resulting in the inhibition of cell migration. tamoxifen is an agonist of th s t n du t on p w , n CA a component of this scaffold, .is thought to be implicated th development of a o it¾n ist nc« during treatment of breast patients. Moreover, the FA C C42 A HGA 2 h been reported to teg a e the formation of l. eg r F aets.n scaffold mp and consequently glioblastomas cell (33). We found that the ar ox i i of AR AF 1 interacts with the carboxyl of sft to release from endoplasmic reticulum through * channels. The interaction of A AP with regulates the formation of F a ti n md E 2 3 ce l migration. Therefore, we propose tha estrogen binds to associated. EE t modulate BCM md eel migration through c~S c CD 42- GA 2I-l s 3R~i«t g ir pathway (Figure 12). EGW binds to er resulting a viti n of the e Sr phosphorylation pathway to regulate cell proliferation t . Anordrin modulation of cell proliferation and has als ee ) demonstrated to act through the c r pathway. We f d that arsofdrin could block the stimulatory effects of EOF on cell n DA B 2 ceils c e l! growth n T47D ce ls When anordrin was used as an antitumor medicine in the it was found to improve the quality of e d the lifespan of patients whose ameers were potentially a by E H r and failed to be inMhited by EOF competitor. Our . that aoordrin can be d in anti-tumor therapies to treat those patients whose tumor growth dependent on br ne ocia ed E and the r l c $rc pathway. GPER has been primarily n to be linked to and-estrogen resistance in reproductive n s since was n to be involved in activation of A /ER and P A T by estrogen through the EGFR pathway EE-negative, but GPERI positive, breast cancer cell lines (34 . Subsequently, it was reported to be adundarnly expressed in biopsy specimens of reproductive cancers fro patients Notably, GPER I expression . s associated with tumor - a - u x ra a ry .metastases (35). However, reports showed i knockdown of GPERI failed to correlate with ERIC activity (36). The GPER l agonist 0 ! also failed to exert an estrogenic effect in the uterus or ma ary gland (37), Oar results show that anordrin is a pore antagonist of n e br e asso ated R functions a a GFERI agonist. In contrast tamoxifen exhibits the opposite properiie«. Eased on our , combination of anordrin and tamoxifen can therefore m z the side effects of tamoxifen. Estrogen regulat o of e has been reported to be primarily d by ER-a. Knockout of E - has e to result in loss of estrogen modulation of obesity (39). 25% of GFER knockout have shown to exhibit obesity (40). I contrast, E β knockout mice do not no d of obesity (41). suggest that cross-talk between ER-a 5 and G E important for the estrogen regulation of energy h e. GPERl predominantly localized to the ret i » , where estrogen and nho h id no itol 3, 4 5 tn pho pha e signals a e d leading to release f m ! $ R (5), White el &l re d that € ai release from ¾ enhances the oene ¾ t of ri (42). the present , we found accumulation of lipid the of liver cells in both 0 ova ecto i ed (0VX) and t o i en reated ice. Taken , we predict that GPERl agonists possibly enhance Jns R activity to deliver from the endoplasmic reticulum to mitochondria, leading to n ed mitochondrial of glucose to ATP. Although GPES as bees found to also to the membrane, crosswalk between G I c hm never n reported. On the other hand, e«trogen~ER~a 5 not only regulates ut-4 i and ts at!o cell n (43), it also cross-talks with IL-IR complex to regulate uptake in MCF d skeletal muscle cells (44, 4 5) . Interestingly, e was found to prevent osteoporosis during clinical usage, An rf r wa also found to prevent osteoporosis in our n (Figure ) cart enhance X iruptake an inhibit ATP generation. The elevated intake of glucose c by tamoxifen cannot be metabolised into APT . e , .glucose can be transformed into TG This of e explains why tamoxifen can Induce NASH when or breast cancer therapy. On the other and, when n of uptiken. glucose cannot be metabolized, amount of TO is stored up, leading to Inhibition of further uptake o glucose even a the presenc o high insulin concentrations. Th s scenario may explain why 5 tamoxifen induces insulin resistance, and thereby increases the incidence of diabetes L . Anordrin or analog thereof ( h as asordrin) can counteract the effects of tamoxifen on glucose glucose metabolism to ATP and TO. Therefore, combination of anordrin and tamoxifen can prevent ta xifen-induced Insulin resistance and incidence of diabetes II. d 50 P a n d construction, protein expression, purification and d acteri a ion b C ER-a igan binding domain and were n into p E X P l at E o an Xhol sites. GS R fusion proteins w re induced using 0.1 PTG and expressed in at :25¾ for 3hours. Bacteria were harvested. fusion proteins were purified following a e instructions. Purified protein GST-heads was doled using IX buffer at X for 5 e . Use was o % SD AGE Gel was stained oo a ie hlu 2 Protein bands were cut and characterised by M SM S and GFE NAs were rc d from YR gene and b o ed i pE t AcGFP d p X CEGF vectors, i C on e ) Cell , trov us packaging, c il sorting a d t of stable eel! r e and drug inhibition assay: CF-7 T47 A- -2 e - , C - and EK-2 3 were grown i ing ATCC protocol l of p S G protein c with -o 3 or G R ! cDNA were o n s c into E -2 3 package Afler 12 n of za c supernatant was nd concentrated using niira ntn f ation at rprn tor 2 on s. Viru sospensed using culture n ed rn of stable ceils. Cells were infected using at 3?¾ for 2 hours grown for 2 days and GFP po i iv cells were seeded into 96we plates at one cell pe we ll . of OFF protein was che ked n blotting. Binding n np t A assays: and - -» fusion to n were expressed in & ii and purified glutathione beads, 2 g GST (4W0rsM) f ion proteins m Iml TE buffer mixed with nM at 4% i r 2h Radioactivity n beads d a GM meter. HER -293 cells were tran fe te to express GST fusion proteins of or PEE Cells were ! ed IX TE buf e containing protease inhibitor cocktail (sig a) on ice for n 8 % glycerol d d to reach 20% glycerol. wer ent fng d at 3 g for S tin and supernatant col cted. a measured by B o rad protein concentration assay kit. ΙΟΟηΜ an rd n d M ¾i~E2 was added to 1 l i sa (S g/ total protein) at 4¾ for 2k Radioactivity o beads w measured using GM meter. Isolation of microsome and Dru g competition assay Ce ls were harvested and lysed in T buffer ( n m ( .0 , nM EDTA, 2 M SF and protease inhibitor cocktail (Sigma)} for 0 with vortexlng every 5 t . 80% .glycerol in T E b r er was added to el! a es to reach 20% n c ri&ged at g for S . The supernatant was transferred to ew tubes and total protein concentration was adjusted to $η¾ 1 Drugs and T-1 E were ad de to 1ml protein and .incubated for 2 . Microsome m precipitated at k pn for 2no Bound was measured using GM eter. Drug in bidon assay; Cells were inoculated into 24 wel plates and treated using the designated concentration of drugs. Cei nu ber was counted using a cell counter (Coun t Star). Tran we ? and flow cytometry assay; Cells -were starved for 4 no rs in phenol red fo d containing 5% charcoal-stripped S , and the changed into phenol red free medium for m additional 24h urs. T a sw performed following the Chemicon ki instructions (CAT#ECM$51). Briefly, cells were r ps n e , washed using X BS containing Ca2 and g2 (Sigma) and re t pen ed and e r d free at a ceil d n of . . 2 µ cell n containing dra wa added nto upper chamber arid inserted the lower chamber containing 0.5ml n edr m with 0 FB for 1 o rs. Flow was p ed y sp i g cells in r psin ee cell suspension buffer Miliip re) and labeling with TC a i ody ( n l npore following company stx ct o& . The specific s A against E - and G R were designed according to references 4 and 47 respectively, and were by G ephar a Co , LTD Glucose concentration assay: glucose con ent ai osi medium or t al blood f om ta l was measured using glucose assay ts following manufacturer * instructions ( ieber g Beijing) Construction of (OYX) mice odel and dn in st ti o of drags: The ovaries of 6 old ice excised 3 days post surgery drugs administered by gastric tract injection every day or with food. Preparations of paraffin sections m d HE staining: The tissue of mice wa excised by fi xed using 2 5% formaldehyde in IX PBS P ra n s n preparation a d HE staining was perforated following the standard protocol from GL laboratory of ni ta . e luc. Measurement of TC and TG In liver and n of mice: 30 S g of liver was excised by surgery and homogenized in lad Cholroforro: ethanol (2: ) i tor m d extracted using .S l ddl¾ . The organic phase was transferred to n w tubes and air dried. The amount of T and T was measured s kits following The error was corrected by internal standard co ro . Bone density assa using icro- T: T ighb was fixed i IX P S ni 3% formaldehyde fo weeks. H e t u was after one week,. e densi ty of thighbone measured by Inveon Mi ro T ve ot Research Workplace (IR ) was used to analyze the I 0 value at following measurement conditions: VP 50 m 00ms ti e; CCD u installation: a 204 8 binning; F V Transaxial: .03mm axial: 9,03mm, pixels size: 9.29p Extraction of eilo r lysate, Western lotting total R A extraction and RT P€ : Ce l were .harvested and y e in Ά buffer or DP containing 1% tr to x 0 n protease inhibitor cocktail. Total protein concentration was -measured using Bio-rad protein staining dy e. Western blotting was perforated following n d protocol using nitrocellulose membrane (Mi I ore ) and Bio-rad -dry transfer te . Total RNA extracted using RNA e solution (sigma). T q CR was performed using the Roche Sy P A I7 0 FCR using the ¾ for mm followed by 40 cycles of 95¾ for t and ¾ or in. Statistical analysis; In ables figures, the sults wer presented as ea S 0 EV. Asterisks indicate a statistically sigai difference calculated using student's te , two-tailed 2 d of ar oro in n dinord Dinordrin has similar structure anordtin that it at R position. We fou d tha o n blocked ¾ H E2 binding to i g of GST ER BD o beads. By , BO inhibition by atiordrin that blocks [ E2j binding to ϊ of GST ~ LBD. Further, 6µΜ d ord r l- nR to i ptio for 147.2 22 73 ( < 0 .. By contrast, statistically tgn 6 a» l i ler t b anordrin 3 3 2 MCF-7 cells was measured using T q CR . The results showed R6 -- 3 opposed to · ) Is e lo the miqm functional characteristics o n rdrin. Paraffin was removed from e liver sections using The liver sections were stained usi g antibodies ag G ER L R or respectively References 1. B ny ataa ako it , St rio s 76, (2 ) a vais-jarvi F.» gg D . a d AL, nd rt Reviews. 34(3), 309-338 20 . a ng G , Zha g XT ie, Y t &1, Molecular endocrinology . 24(4), 09 (20 ) 4 . J , J! M,, Wang , Y.s B„. Journal of Steroid Bi c mt md Molecular Biology 127 23 237 (201 ) . Revankar, CM Ct o ar, LA., Ar rb r B. ¾nd oss t Eft... Science. 307 ) , 2 - 3 2005 6 J on, O , Qlde ¾B . L Lu.ndberg, LF British Journal of Pharmacology. 163 39 20 ) 7. XT , D ng, L ang .LG and Wang, Y.. PLos ?( I), «30 4 (20 ) 8 . B i ea JE..> Pete rso ί T g , et a . of BioL h 2 (36) . 26683-26692 (2006) Takara r T htnti A . u ra . Arsdo, Zen, Y., et si. Internal Med. 579-581 (2007) 10. Barrett-Connor, E . osca L., i et ai Engl. J Med.. 355. 125-137 (2006) A xa d rsoa ,, T s a A., sto et JAMA. 285( 1) 1482-8 (21)01) 12. H rshberg r PA., Stabile, LP., a er tez B., et al... 1 of Steroid Bioc e & Mol Biol 1 6 . 102-9 {2000) 13. Ba k U.K. and Pin , , Pro , . Expt. Biol. Med. 1 , 50 (1062). 14. a . Gordon, . ., Steroids, 5, , (1965). . X 8., Zhou, P.Q Yu., W , , , 9? (1989). 16. Ma, Z.C., Lou, L.G. Zhang, Z and Βί η X, Pharmacol. Sin, 2 1, 939 (2000). 17. .L , Lee, .Y. , US $00 20 991). 18 M hta R.R., J nco 3 M. and hatt r on . , Steroids, 3 , 679 . 19 ra R., R ggi s B. S aj ah n AN et a... FASEB J. 24(6). 2040-55 (2010) 20. Watar a T. none tr ., Oriroo, A. et al .. Mol. Cell. Biol. 18.442-9 (1998) 2 . Butler, WB sey, SJ C tagaa, M and Slumbers, ΡΜ . Cancer Res 4 ( 1). ( !9 1) 22. Cesarone G, Gar fa C, Abrams MT, a l .. J Cell. Bio he 98( ) 440 5 (2006 ) 23. ang, G Zhang, XT . X , Y. T , ,, et a l . . Mo . Endocrinol., 24(4) 709-21 (2 0) 24. Zhang, I L , G L , , , X., Z ang, L et al... Stero ids 77(6) 666 73 (2012) 25. Melchiori. A. orta R., a f ne, $ al.. Exp . ¾ ¾¾ 219, 233-242(1995). 26. or ni ., otto se M., Ferrari, , G ior o, . et al. I t . Cancer: (2000) 27. Ga i d P, Moran J, .A ns A, l S, et al.. Endocrinology. 154(6): 1979-89 (2 ) 28. G DR., and Garrls, L. Cell Tissue , 319 (2) 2 -42 (2005) 2 9 . Wang Q., Jiang, L , Wang, 1. ei al.. Bepato! g . 49. 66-75 (2009) 30. $¾atk $ Par s, IB , Quadid A do h i et al ! Caneer 9 6(2 10) . B&nnai , o T, iko Iii J e roc . 1.4(6): 720-33 (2010) 32. Cabodi, $., Mom, L, Baj G al. Cell S . 117. 03- ! 1 (2004) 33. Bigarella CL Berg s L Costa F, Saad ST. Bioch Bioplivs Acta. ! 793(S);S06-!6. (2009) 34. F rdo Quint* f A, Bland F k o Jr. A . M ol Endocrinol. 14: 649-60 (2000) 35. Filardo J Graeber T Q JA t al .. C . Cancer Res. 12:6359-66 (2006) 36. Pe ra A, to n i M, Levin ER Mol. Endocrinol. 20: 996-2009 (2006) 37 Otto Ro de sc d B, S h a z GF chs I, et al Endocrinology. 149:4846-56 (2 ) 38 Edward 3, Filardo Thomas P Endocrinology, 1.53(7): 2953-62 (2 2) 39 Geary, , Asa an L., Ko c , KS et al. E docrino gy . 42, 4751 -7 (2001) O sso berg, , P r i et s . 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En . a Cancer, 2): 355-69 (2014). .AIMS A method of treatin ca cer " an divi al o p ing to i u l ua ti aa of f ano r or an thereof. 2, The method of claim , further administering to the individual a effective amount of at least one oilier agent selected the groap consisting of tamoxifen raloxifene fc iv le i , a»d an ar t inhibitor. 3 method of r side effect of at least one other agent by a rdr comprising adm tering to the iadiv al a effective amount: of anordrin o aa analog re ia combination with agent, wherein the other agent is selected fr m the group i of tamoxifen, raloxifene or functional equivalent thereof, and an aro atase Is hi r 4, The method according to any o of clai 2 or wherein said other age t tamox f n. 5 The according to one of ta t. 2 or , wherein the other agent is raloxifene or functional equivalent thereof 6 . The method claim 2 or , wherein the other agent raloxifene. ? The method according to claim or , wherein the other age t is se from the group consisting of raloxifene i sofo i , ba edox fene o nelo lf n ospe fe e and levo tetox fese The method according to any of 2 or » wherein the other agent is a aro a a e inhibitor. 9 The method according to claim 8, wherein the arornatase inhibitor is ana ro oJe. . The method according to claim 8 wherein the aroa a a e inhibitor is selected from the group consisting of: anas r sol letro le voroKo!e for t ne, and f droxo! The method rd to an mm of claims , wherein the cancer is selected from the group consisting of hreast cancer, lung , gastric a r colon cancer, and CLL. 2 The method according to m y one of 2- , wherein the cancer res t nt to treatment with other agent when not administered in combination with ano d i 3 The according m y of c 1-12, wherein the individual is positive for e a s receptor. 14 The method according to on of claims 1 13 wherein the individual is positive for VEG or EGF 5 The h according to one of claims 2- 4 wherein the a ord n the other agent administered sequentially 16 method according t any one of 2 14, whereto the ano r ft and other agent are administered simultaneously. The method according to one of claims I- 6, wherein the individual is a human, 18 The .method n to anv one of claims 1-1. , w n the an r n or an thereof is nordr a . 19, A method of reducing a postmenopausal symptom i an individual, comprising administering to the individual an effective amount of an an rdri or an analog thereof. 20 The method according to claim 19, further co pr g administering to the individual an effective amount of at least one other agent, wherein the othe agent is raloxifene or functional thereof. 21, The method according to clai 20, wherein the other agent is raloxifene. 22. The method according to claim , wherein the other agent is selected from the group of raloxifene , b edoxifene. a x ene o te oxifene o pc if n , and l vonn io fen 23. The o i to any n of 9-22 wherein the postmenopausal is selected from the group consisting of fat liver, weight gain, high blood triglyceride, a d r n organ atrophy. 24. The according to any one of . 20-23, where the anord n and the other agent ar administered sequentially.. 25. The method according to any one of clai s 20-23, wherein the anordrin and the oilier agent are si u aneo sly 26. The method according to any o e of m I 25, wherein the individual is a m 27. The method according to any one of claims wherei the an n or analog thereof is at ordrin 28. A pharmaceutical position o a ordri or an analog thereof and at least one other agent: selected from the group consisting of a raloxifene or functional equivalent thereof, an an a o at e inhibitor 29. The pharmaceutical composition according to claim 28, wherein said other agent is fe 30. The pharmaceutical composition according to clai 28, wherein the other agent i raloxifene or functional n thereof The pharmaceutical composition according to claim 28, wherein the other agent is raloxifene. 32 The pharmaceutical d to claim wherein othe agent is selected fro group consisting of raloxifene., iaso ifene b edo fene ar oxi ene o lo f ne . o if ne, i vor loxif e 33 The pharmaceutical composition according to claim 28, wherein the other is an aro e nbibito 34 The composition according to claim S3 the a o a a inhibitor s a as o !e 35 The pharmaceutical composition according to claim 33 wherei the ar ata e inhibitor is selected from the ou consisting of: n r et o , ex tn stane or zole, f rmest ane a»d adro ol .- 36 The pharmaceutical composition according to my one of claims - further comprising lipi d 3 The pharmaceutical composition according to an one of further comprising casein 3 The composition according to any one of claims 28-37, re the weigh ratio of anordr and the other agent in the composition is about 20:1 to about :20 39 An oral unit dosage form comprising the h t composition according to . one of claims . 40 The oral unit dosage or n according to clai 3 wherein the un t dosage form is n the form of tablet. INTERNATIONAL SEARCH REPORT International application No. PCT/CN2015/077942 A. CLASSIFICATION OF SUBJECT MATTER A61K31/56(2006.01)i; A61P 35/00(2006.01)i; A61P 15/12(2006.01)i; A61P l/16(2006.01)i; A61P 3/04(2006.01)i; A61P 3/06(2006.01)i; A61P 19/10(2006.01)i According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K;A61P Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) Data base: WPI, EPODOC, CNPAT, Chinese patent full text search system, CNKI, EMBASE Search terms:anordrin , analog , cancer, tumour,tumor,neoplasm,tamoxifen, xifen, raloxifene, aromatase inhibitors , anastrozole, postmenopausal, C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. PX CN 104208069 A (SHANGHAI INSTITUTE OF PLANNED PARENTHOOD RESEARCH) 1-40 17 December 2014 (2014-12-17) see the whole document X Gu Jian, et al. , . ""Comparison of antitumor effect of a-anordrin and its metabolite 1, 11 , 17-18 AF-45", " TUMOR, , Vol. number 2 , , No. volume 14, , 31 March 1994 (1994-03-31), ISSN: ISSN: 1000-7431 , , pages 66-69 A Gu Jian, et al. , . ""Comparison of antitumor effect of a-anordrin and its metabolite 2-10, 12-16, 19-40 AF-45", " TUMOR, , Vol. number 2 , , No. volume 14, , 31 March 1994 (1994-03-31), ISSN: ISSN: 1000-7431 , , pages 66-69 I IFurther documents are listed in the continuation of Box C. | | See patent family annex. Special categories of cited documents: later document published after the international filing date or priority "A" document defining the general state of the art which is not considered to be of particular relevance date and not in conflict with the application but cited to understand the principle or theory underlying the invention earlier application or patent but published on or after the international filing date document of particular relevance; the claimed invention cannot be "X" considered novel or cannot be considered to involve an inventive step document which may throw doubts on priority claim(s) or which is when the document is taken alone cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is document referring to an oral disclosure, use, exhibition or other "O" combined with one or more other such documents, such combination means being obvious to a person skilled in the art document published prior to the international filing date but later than document member of the same patent family the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report 17 July 2015 05 August 2015 Name and mailing address of the ISA/CN Authorized officer STATE INTELLECTUAL PROPERTY OFFICE OF THE P.R.CHINA WANG,Huiyan 6, Xitucheng Rd., Jimen Bridge, Haidian District, Beijing 100088, China Facsimile No. (86-10)62019451 Telephone No. (86-10)62411126 Form PCT/ISA/210 (second sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No. PCT/CN2015/077942 Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Claims Nos.: 1-27 because they relate to subject matter not required to be searched by this Authority, namely: [1] The subject matter of claims l-27relates to a method of treatment of the human or animal body by therapy and therefore does not warrant an international search according to the criteria set out in Rule 39.1(iv)PCT.The search has still been carried out and based on the corresponding uses of the compound/composition in preparation of medicaments. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: [1] Group I: claims 1-18 , which relate to a method of treating a cancer, and a method of reducing side effect of at least one other agent. [2] Group II: claims 19-27, which relate to a method of reducing a postmenopausal symptom. [3] Since anordrin is known from prior art,consequently the above two groups of inventions lack unity of invention and do not meet the requirements of unity of invention as defined in Rule 13. 1 PCT. 1. I I As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. I I As all searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment of additional fees. 3. I I As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. I I No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest | | The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. I I The additional search fees were accompanied by the applicant' s protest but the applicable protest fee was not paid within the time limit specified in the invitation. I I No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (Continuation of first sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No. Information on patent family members PCT/CN2015/077942 Patent document Publication date Publication date Patent family member(s) cited in search report (day/month/year) (day/month/year) CN 104208069 17 December 2014 None Form PCT/ISA/210 (patent family annex) (July 2009)