175:1

J S Carroll ER regulation in breast 175:1 R41–R49 Review cancer

Open Access

EJE PRIZE 2016 Mechanisms of oestrogen (ER) gene regulation in

Correspondence should be addressed J S Carroll to J S Carroll Email Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK [email protected]

Abstract

Most breast cancers are driven by a factor called oestrogen receptor (ER). Understanding the mechanisms of ER activity in breast cancer has been a major research interest and recent genomic advances have revealed extraordinary insights into how ER mediates gene transcription and what occurs during endocrine resistance. This review discusses our current understanding on ER activity, with an emphasis on several evolving, but important areas of ER biology.

European Journal of Endocrinology (2016) 175, R41–R49

Introduction

Oestrogen receptor (ER) is a that functions, such as pregnancy, is a co-ordinated process European Journal European of Endocrinology regulates events that culminate in cell that involves other and their division, an important property that contributes to its transcription factors, including progesterone and critical role in mammary gland development. ER is a prolactin (2). member of the nuclear receptor superfamily, which The ability of ER to associate with DNA and initi- comprises 48 proteins (1) that have a diversity of roles ate gene transcription is subverted in disease, where ER and are major contributors to the functioning of the becomes a driving transcription factor that is no longer . As a nuclear receptor, ER has a DNA- regulated by control mechanisms, and this results in an binding domain (DBD) that enables it to directly regulate oestrogen-induced tumour. Essentially, ER continues to gene expression events and a ligand-binding domain operate in its normal role as a gene regulating transcrip- (LBD) that renders it responsive to an activating ligand, tion factor, but the ER-mediated cell division occurs in namely oestrogen. The role of ER in initiating timely an uncontrolled manner, resulting in tumour initia- and controlled cell division during mammary gland tion and cancer progression. Three quarters of all and during post-pubertal physiological cancers (~37 000 out of 50 000 new cases in the UK per

Invited Author’s profile Dr Jason Carroll was born in Australia and completed his PhD degree in Sydney at the Garvan Institute. He then did postdoctoral work with Prof Myles Brown at Dana-Farber Cancer Institute at Harvard Medical School. Dr Carroll joined Cancer Research UK, University of Cambridge as a group leader in 2006 and is currently a senior group leader and a Fellow at Clare College, University of Cambridge. His main research interest is in understanding how oestrogen receptor (ER) regulates gene expression in breast cancer and recently has been focussing on delineating the hormonal cross-talk that exists between ER and other hormonal nuclear receptor pathways.

www.eje-online.org © 2016 The authors This work is licensed under a Creative Commons DOI: 10.1530/EJE-16-0124 Attribution 3.0 Unported License

Downloaded from Bioscientifica.com at 09/28/2021 09:01:49PM via free access

Doi: 10.1530/EJE-16-0124 Open Access J S Carroll ER gene regulation in breast 175:1 R42 cancer

annum) (source: Cancer Research UK) are character- showing that in the absence of ER, AR can substitute ized by the presence of ER. These cancers are therefore for ER and initiate cell division in an ER-independent, defined as ER+ and these women as candidates for spe- but nuclear receptor-dependent manner (10, 11). The cific treatments that block ER activity. One of the first bulk of drug-resistant breast cancers retain the expres- targeted agents in the treatment of cancer was the selec- sion of ER (8) and this transcription factor complex tive oestrogen receptor modulator (SERM) tamoxifen, gets re-engaged even in the presence of an endocrine which is an effective treatment for ER+ breast cancers agent that inhibits the ER pathway. There are a number (3) because it can mimic oestrogen and bind to the LBD of mechanisms a cancer cell can utilize to circumvent pocket of the ER, but unlike oestrogen, it alters the struc- either an ER-blocking chemical (i.e. tamoxifen), low ture and function of ER so that this transcription factor levels of ER (i.e. Fulvestrant) or low levels of oestrogen is no longer capable of regulating gene expression (4). It (i.e. AIs), and these include: 1) changes in the levels has been estimated that almost half a million women are of associated proteins that are required for ER tran- alive today because of the use of tamoxifen in the treat- scriptional activity, termed co-factors (these will be dis- ment of ER+ breast cancer (5) and although tamoxifen cussed later); 2) upregulation of growth factor pathways has been the mainstay for the treatment of ER+ disease that can initiate or promote ER transcriptional activity for numerous years, many women develop endocrine via kinase signalling pathways that phosphorylate tar- resistance and tamoxifen subsequently fails. This led get proteins to render them more active; 3) changes in to the development of novel agents that block ER func- drug metabolism and cellular secretion and 4) changes tion, resulting in pure steroidal antioestrogens, such as in the fidelity of the key proteins involved in the ER Fulvestrant (Faslodex) and a class of compounds termed complex. Excellent reviews on the mechanisms of aromatase inhibitors (AIs). Fulvestrant binds to the LBD endocrine resistance have been described in other stud- of ER, but unlike tamoxifen, it induces degradation of ies (12, 13). Recent findings have shown that 18 – 55% the ER protein, and this drug has been an effective treat- of metastatic samples harbour in ER (ESR1) ment in tamoxifen-resistant contexts (6). In pre-meno- and these mutations occur in predictable pausal women, the major source of oestrogen is ovarian residues in the LBD of ER, decreasing the dependence production, but in post-menopausal women, the bulk of on oestrogen and the response to targeted treatments the oestrogen is metabolized from chemical precursors (14, 15, 16). Given the highly fecund nature of cancer by an enzyme called aromatase. AIs work by blocking cells and the general genomic instability of these cells, this metabolic step, essentially starving the cancer of its it is unsurprising that mutations and genomic altera- European Journal European of Endocrinology ligand, oestrogen. These different classes of drugs inhibit tions accumulate at a regular rate in cancer, making the ER function, but they take distinct routes, meaning that disease a constantly evolving, moving target. resistance to one type of drug does not necessarily ren- der other classes of compounds redundant and as such, Mechanisms of ER association with DNA in breast cancer different endocrine agents are used sequentially for the treatment of ER+ breast cancer. Understanding how ER initiates tumour formation The majority of women with ER+ disease will ben- is of paramount importance since it is likely that efit from targeted drugs that block the ER pathway, but the underlying mechanisms that govern ER tumour one-third of women will develop drug resistance (7). formation are altered during the transition to drug Understanding the mechanisms of drug resistance is a resistance and metastasis. Decades of research have long-standing question and it is clear that cancers can revealed extraordinary insights into how ER functions, circumvent ER-blocking agents via a number of differ- with a complex picture emerging. Many of the facets of ent mechanisms. During the process of drug resistance, this mechanism of ER transcriptional activity are retained the tumour continues to grow and metastasizes to a and conserved with other nuclear receptors in cancer. secondary organ, particularly the bone, liver, brain and This is particularly the case in prostate cancer, where lung, where survival is compromised. A small fraction of AR is the driving nuclear receptor and consequently, tumours (~10 – 20%) lose ER expression (8) and there is substantial parallels exist between AR-mediated prostate evolving evidence that additional nuclear receptors can cancer development in men and ER activity in breast substitute for ER in this situation. Specifically, andro- cancer in women. gen receptor (AR) is known to be expressed in 80 – 90% For many years, ER was thought to be a stand-alone of ER+ breast cancers (9) and there is a recent evidence transcription factor, which in response to oestrogen

www.eje-online.org

Downloaded from Bioscientifica.com at 09/28/2021 09:01:49PM via free access European Journal of Endocrinology transcription factorsthatcan assistintetheringERto elements occupiedbyER. These includedanumberof implying afunctionalconnection attheenhancer DNA bindingmotifswithin theregionsboundbyER, identified bytheover-representation oftheirconsensus the ER complex on the . These factors were also interactwithDNA and contributetostabilizing sites uncoverednovelER-associatedproteins,which Interrogation of the thousands of ER-DNA interaction considerable distancesfromtheputativetargetgene( associates withenhancerelementsthatcanbe at unbiased mapping approaches showed that ER typically to associatewiththepromotersoftargetgenes,but cancer celllinemodels( unknown ER binding sites wereidentifiedfrombreast and subsequentlybyhigh-throughputDNAsequencing, and identifyingtheassociatedDNAbytilingmicroarrays method called chromatin immunoprecipitation (ChIP) ER-associated DNA(i.e.thegenomicbindingsites)bya assess ERfunctioninanunbiasedmanner. Bypurifying genomic technologiesprovidedthefirstopportunityto and regulatetranscription( revealed insightintohowERcaninteractwithDNA crine therapies. of circumventing theanti-proliferative actionofendo co-factors ( or negativewaybychangesincriticalbutrate-limiting that ERtranscriptionalactivityispushedinapositive ( ferent co-factorsandtheirrolesinER bly andactivity. Anumberofreviewsdescribethedif properties thatarerequiredforoptimalproteinassem tors and numerous co-factors that have enzymatic proteins thatprovideplatformsforotheressentialfac making the compacted DNA accessible for ER to bind, tions. Theseinclude the ability to ‘open’chromatin, dozens ofco-factorsthatperformamultitudefunc ER activityrequirestheco-ordinatedaccumulationof permit transcriptionalregulation.Itisnowclearthat insightintothecomplexesthatformwithERtodinary quent characterizationofthesefactorsrevealedextraor of ER-associatedco-factors( (ER) the sole determinants of its activity. The discovery hence makingtheligand(oestrogen)andreceptor was purportedthatERcouldinitiategenetranscription, tides (GGTCAnnnTGACC)( inverted sequencesseparatedbythreerandomnucleo lished ERconsensusDNAsequenceiscomposedoftwo was abletodirectlyinteractwithDNA.Awell-estab 21 Open Access , The studyofasmallnumberERtargetgenes 22 ). Thelevelsofkeyco-factorscanbealteredsuch 20 , 23 ), and this hasbeena documented way 26 , 27 24 17 18 , , ). OnceontheDNA,it , J SCarroll 28 25 19 , ), buttheadventof , 29 20 ). ERwasthought ) andthesubse + breastcancer 26 ). ). ------that asubsetofthemanytensthousandsER–DNA and genome-widemappingofthesefactorshasrevealed functional, transcriptionally active ER bindingelement of these(andother)importantco-factorsdemarcate a such asAIB1,p300andCBP( binding enhanceristhepresenceofassociatedco-factors, regulated. AnindicatorofatranscriptionallyactiveER binding eventswereactiveandwhichgenetargets enhancers ( proximalregionsandinsteadoccuratdistal ER interactionswiththechromatin. contribute, tosomedegree,increatingormaintaining ER–DNA interactionsareperturbed.Assuch,theyall protein isspecificallyinhibitedinbreastcancercells, these factors( required or what degree of redundancyexistsbetween ( the DNA,includingFOXA1,GATA3, PBX1andAP2 motifs withinERbinding sites( FOXA1 was discovered by the enrichment of Forkhead FOXA1 andGATA3 in breast cancer are, isanimportantquestionforfutureresearch. coding RNAsareimportantandwhattheirpotentialroles but potentiallyplayfunctionalroles.Definingwhatnon- which becomeRNAsthatarenottranslatedtoproteins, transcribed in response to oestrogen stimulation, much of proportion ofthegenomeabreastcancercellline is actual siteofERoccupancy( ing enhancerRNAs (eRNA) thatareproducedfromthe to localizedtranscriptionofnon-codingRNAs,includ associates with elements can also contribute late codinggenes,buttheER–DNAbindingcomplexthat the ER complex reach over significant distances to regu plexity tothissystem,itisnowclearthatnotonlycan ER bindingeventsandtheirtargetgene( global snapshotoftheinteractomethatoccursbetween approaches havebeendeveloped,whichprovideathe est oestrogen-regulatedgenepromoter( interactions, suchasanER-bindingdomainandtheclos approaches canbemadetoinvestigatespecificchromatin and promoters of putative target . Candidate-based ( by exploitingmethodsforidentifying chromatin loops been anadditionalchallengethathasapproached ing site(thatistypicallyfarfromanycodinggene)has target genesareinducedorrepressedbyaspecificERbind contact sitesaretranscriptionallyactive.Identifyingwhat cancer ER 36 26 generegulationinbreast ) thatformbetweenenhancers(ERbindingsites) , Given thatmost(~95%)ERbindingsitesarenotat 30 , 31 , 27 32 ), achallengewastoidentifywhetherallER 33 ). Itisunclearifalloftheseproteinsare ), butwhenanyoneoftheseindividual Downloaded fromBioscientifica.com at09/28/202109:01:49PM 39 25 , 40 , 34 ). Asurprisinglylarge 26 175 , , 35 www.eje-online.org 26 :1 38 41 ). Thepresence , ). To addcom 37 ). FOXA1is ). Unbiased R43 via freeaccess γ - - - - -

Open Access J S Carroll ER gene regulation in breast 175:1 R44 cancer

termed a (42) since it has the ability to Specific inhibition of GATA3 in breast cancer cells pushes occupy compacted DNA without the requirement for ER towards new DNA binding sites that are demarcated any additional proteins (43, 44) and can subsequently by FOXA1 (52), suggesting that GATA3 might function facilitate interactions between additional factors (such as as a rheostat, dictating possible ER–FOXA1 interactions. ER) and the DNA (26). FOXA1 was shown to be required Total loss of GATA3 in mice mammary glands results in for all ER binding sites in models of ER+ breast cancer, tumour progression and GATA3 was proposed to be a criti- and was also shown to be required for ER binding and cal protein influencing and tumor- growth of endocrine-resistant breast cancer cell line igenesis (53, 54). Interestingly, FOXA1 was shown to be models (45). Immunohistochemistry of ER and FOXA1 a downstream target of GATA3 in the murine mammary in metastatic tumour material showed that FOXA1 is gland (53). GATA3 has been shown to be required for the expressed in almost all solid distant metastases, and that morphogenesis of normal mammary glands (55), sug- correlation between ER and FOXA1 protein expression is gesting an important role in promoting cellular differen- high (46). The dependence on FOXA1 for ER function, tiation, inhibiting proliferation and contributing towards even in endocrine-resistant contexts (45) creates a novel the development of functional mammary glands. In ER+ opportunity for therapeutic intervention, whereby breast cancer cells, silencing of GATA3 inhibited prolifera- targeting the pioneer factor, namely FOXA1, instead of tion (30), suggesting a dependence on GATA3 for main- the nuclear receptor (ER) might provide an opportunity tained proliferation of ER+ cancer cells. These findings for blocking ER transcriptional activity. Acquisition of provide a complex picture of GATA3 function, whereby activating ESR1 mutations, changes in co-factors levels or it mediates cellular differentiation in normal mammary upregulation of growth factor pathways can all enable ER gland, but becomes an essential component within the ER to activate gene expression in the presence of drugs, but complex during tumour formation. all are dependent on ER making contact with the DNA. As discussed above, ESR1 (ER) is commonly mutated Inhibition of FOXA1 would theoretically circumvent in the metastatic context, but it is rarely mutated in these mechanisms associated with drug resistance, by primary tumours within the breast. FOXA1 and GATA3 destabilising ER–chromatin interactions. However, on the other hand are mutated in primary breast cancer transcription factors are notoriously difficult to drug (56, 57, 58). GATA3 is one of the most frequently mutated and a more realistic option might be the identification genes in breast cancer, with 14% of ER+ cases harbouring and subsequent therapeutic manipulation of upstream GATA3 mutations. Recent data have shown that tumours regulatory enzymes that influence FOXA1 function. The that enrich cells with GATA3 mutations tend to be ductal European Journal European of Endocrinology related protein, FOXA2, is known to be phosphorylated by cancers, whereas tumours that possess FOXA1 mutations the AKT pathway, which influences its cellular localization tend to be of the lobular subtype (58). This distinction and function (47), although it is known that FOXA1 is not suggests that specific breast cancer subtypes are more tol- regulated by AKT (47). A concerted effort in identifying erant of mutations in certain ER components and func- and characterizing FOXA1 regulatory enzymes is of tionally do not benefit, or survive, from mutations in paramount importance, given the evolving information other components. It is currently unclear what the muta- linking FOXA1 with ER activity and the opportunity to tions in FOXA1 and GATA3 do to the function of these block ER via its critical and necessary pioneer factor. proteins and what effects these perturbations have on ER The third protein in the triumvirate of the ER complex transcriptional activity. FOXA1 mutations tend to occur is GATA3. ER, FOXA1 and GATA3 are three of the defining in the DNA-binding domain (57), and preliminary data signature genes consistently observed in ER+ breast can- from prostate cancer suggest that mutations in FOXA1 cers (48, 49), and all three proteins have been shown to be decrease AR signalling and increase tumour growth (59). required for the establishment of an oestrogen-responsive GATA3 mutations can be roughly divided into two major ER complex (50). Insights into the architecture within classes: the first being within the second DNA- the ER DNA-binding domain was revealed by fine resolu- binding domain of GATA3 and the second class being tion transcription factor mapping (51). This showed pre- C-terminal mutations that commonly induce frame shifts dictable spacing between the motifs for ER, FOXA1 and and an altered GATA3 protein (56). Whether both classes GATA3, suggesting that all three proteins must be able of GATA3 mutations have the same effect on ER transcrip- to associate with the adjacent pieces of DNA for them to tional activity and tumour outcome is currently unclear, co-operate and form an oestrogen-responsive complex but recent gene editing tools, such as CRISPR technolo- that is capable of generating a stable DNA interaction. gies, will permit investigation of these questions.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/28/2021 09:01:49PM via free access European Journal of Endocrinology been madebetweenglucocorticoid andER( of ERproteinlevels( rate-limiting co-factorsorpotentially throughregulation actions by AR or PR ( ferent ways,includingdirectalterationofER–DNAinter ER transcriptionalactivitycanoccurinanumberofdif ER pathway( ER shown asubstantialdegreeofnuclearreceptorcrosstalk in reflect thephysiologicalsituations.Recentfindingshave than itscognateligand(oestrogen)doesnotaccurately receptor, such asER,intheabsenceofallhormonesother factors andotherstimuli,thestudyofasingle-nuclear cer isexposedtoacomplexmilieuofhormones,growth progesterone alone,respectively. However, ER have beenconductedinthepresenceofoestrogenaloneor ing ERfunction,orPRfunctioninbreastcancermodels nuclear receptorandalmostalltheliteraturecharacteriz quences. Thishasproventobeusefulforstudyingaspecific to study a single and the downstream conse ‘strip’ outallhormonesfromthegrowthmedia,inorder systems thatbetterrepresentER resistance and for evaluatingnovel agents using for discoveringthemechanismsthatcontributetodrug of PDXmodelshascreatedanoutstandingopportunity more aggressiveER engraft inmice,suchasPDXtumours,tendtobethe tumours that typically disease, although the primary numerous additionalmodelsfortheinvestigationofER patient-derived xenograft(PDX)tumours,whichprovide ER tumour samples ( from ERChIP-seqexperimentscarriedoutinprimary made cell linemodelaccuratelyreflecttheobservations the propertiesassociatedwithERbindingeventsfromthis tumours,and line modelsarecriticalfactorsinprimary associated transcriptionfactorsdiscoveredinthesecell tumours( genes inprimary ( ofthemostrobustoestrogen-regulatedgenes discovery of informationaroundERfunction.Thisincludedthe line, whichhashelpedtoresolveasubstantialamount The ‘workhorse’inthefieldisMCF-7breastcancercell that areresponsivetoendocrinedrugtreatmentexists. scarcity ofmodels.AlimitednumberER The ER hormonal crosstalk Models ofER 60 Open Access + + , breastcancer, withbothPRandARconvergingonthe cancerarebecomingavailable,intheformof The use of cell line models has permitted the ability to The useofcelllinemodelshaspermittedtheabilityto 61 , + breastcancerresearch fieldishamperedbythe 62 ), which are validated as important signature 9 + breast cancerandthecomplexityof , 67 46 , 68 + ). More complex models representing cancers ( , i. 1 Fig. 69 69 , , 70 70 63 ). Similar observations have have ). Similarobservations ). The impact of AR or PR in ). TheimpactofARorPRin ), through sequestration of ), through sequestration of , 66 64 + disease. J SCarroll ). That said, theadvent , 65 ). Theco-factorsand + PR + breastcan 71 + celllines ), where ), where in vivo + - - - - -

that different nuclear receptors can sometimes substitute that differentnuclearreceptorscansometimessubstitute the same cellular environment is highlighted by the fact plex. Theabilityofnuclearreceptorstointeractwithin quently thetargetgenesthatareregulatedbyERcom GR isabletoinfluenceER–DNAbindingsitesandsubse FOXA1 ligands fortherapeuticuseand howthemutationsin involves identifyinghowwecan exploitexistingPRandAR to impingeonERtranscriptional activity. Amajorchallenge commonly expressedinER (PR)andandrogen(AR)are different nuclearreceptorshasbecomeapparent. activity isnotknown.Recently, thecrosstalkbetween metastases. TheimpactthatthesemutationshaveonER mutated inprimarycancers,whereasERis include FOXA1andGATA3. BothFOXA1andGATA3 are DNA. Two criticalproteinsinvolvedintetheringERtotheDNA Oestrogen receptor(ER)usespioneerfactorstoassociatewith Figure 1 cancer ER PR generegulationinbreast andGATA3 influencethishormonal crosstalk. PR FoxA1 ER + Downloaded fromBioscientifica.com at09/28/202109:01:49PM breastcancerandbothareknown ER = mutaon GATA3 175 www.eje-online.org AR :1 AR Gene ER R45 , via freeaccess - - Open Access J S Carroll ER gene regulation in breast 175:1 R46 cancer

for one another. A subtype of breast cancer called molec- inform our understanding of other diseases (such as ular apocrine, which comprise ~4% of all breast cancers, prostate and ovarian cancers), and the tools, technologies is characterized by gene expression signatures that are and biological observations need to be translated similar to ER+ subtypes (72, 73), but these cancers are ER and exploited in diseases with common underlying negative. In this specific subtype of cancer, it is believed pathological properties. that AR can substitute for ER and can become the driv- ing transcription factor, where it continues to regulate ER Declaration of interest target genes because FOXA1 recruits AR (instead of ER) to I declare that I do not have any conflict of interest. the enhancers normally occupied by ER. Similarly, there is evidence that following AI treatment, a resistance mech- anism involves down regulation of ER and subsequent Funding mobilization of AR as the driving factor (10, 11). These Funding was received from Cancer Research UK and the funding code is ‘core funding’. findings provide the impetus to study ER in the presence of physiologically accurate hormonal conditions. The existence of hormonal crosstalk also reveals novel oppor- tunities for therapeutic intervention, whereby parallel References pathways are potentially drugged to indirectly regulate 1 Germain P, Staels B, Dacquet C, Spedding M & Laudet V. Overview ER activity. Future work will identify who would gain the of nomenclature of nuclear receptors. Pharmacological Reviews 2006 58 685–704. (doi:10.1124/pr.58.4.2) most benefit from PR or AR-targeted drugs for the treat- 2 Brisken C & Ataca D. Endocrine hormones and local signals during ment of specific ER+ breast cancer cases, a hypothesis that the development of the mouse mammary gland. Wiley is supported by a wealth of clinical data showing that Interdisciplinary Reviews: Developmental Biology 2015 4 181–195. (doi:10.1002/wdev.172) PR agonists have efficacy in breast cancer patients selected 3 Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, only based on ER+ status (74, 75, 76, 77, 78, 79, 80, 81, 82). Robidoux A, Bevers TB, Kavanah MT, Atkins JN, Margolese RG et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Concluding remarks study. Journal of the National Cancer Institute 2005 97 1652–1662. (doi:10.1093/jnci/dji372) The research community has studied the ER pathway 4 Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA & Greene GL. The structural basis of receptor/coactivator for decades and the findings have revealed a complex recognition and the antagonism of this interaction by tamoxifen. Cell picture, where ER associates with hundreds of proteins, 1998 95 927–937. (doi:10.1016/S0092-8674(00)81717-1) European Journal European of Endocrinology interacts with thousands of regions in the genome and 5 Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nature Reviews Drug Discovery 2003 2 205–213. (doi:10.1038/ can regulate a multitude of target genes and non-coding nrd1031) RNAs, many of which are only now being identified. The 6 Howell A. The future of fulvestrant (‘Faslodex’). Cancer Treatment findings from the study of this pathway have identified Reviews 2005 31 (Supplement 2) S26–S33. (doi:10.1016/j. ctrv.2005.08.007) the mechanisms of drug resistance and novel ways of 7 EBCTCG. Effects of chemotherapy and hormonal therapy for early targeting this disease, which has translated to improved breast cancer on recurrence and 15-year survival: an overview of the survival rates in women with this disease. The advent of randomised trials. Lancet 2005 365, 1687–1717. (doi:10.1016/S0140- 6736(05)66544-0) immunotherapy in combination with existing and novel 8 Harrell JC, Dye WW, Allred DC, Jedlicka P, Spoelstra NS, Sartorius CA targeted agents is likely to improve the survival rates & Horwitz KB. positive breast cancer metastasis: even more, but women with ER+ breast cancer continue altered hormonal sensitivity and tumor aggressiveness in lymphatic vessels and lymph nodes. Cancer Research 2006 66 9308–9315. to die and as such, the research community needs to (doi:10.1158/0008-5472.CAN-06-1769) continue the exploration of this important pathway. The 9 Peters AA, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera use of better models (i.e. PDX) will contribute to this MM, Harris JM, Jindal S, Segara D, Jia L, Moore NL et al. inhibits estrogen receptor-alpha activity and is prognostic in and, importantly, our ability and motivation to study breast cancer. Cancer Research 2009 69 6131–6140. (doi:10.1158/0008- drug resistance by analysing metastatic material and 5472.CAN-09-0452) using models of metastasis is of paramount importance, 10 Ni M, Chen Y, Lim E, Wimberly H, Bailey ST, Imai Y, Rimm DL, Shirley Liu X & Brown M. Targeting androgen receptor in estrogen as evidenced by the recent observation that ER itself is receptor-negative breast cancer. Cancer Cell 2011 20 119–131. frequently mutated in metastases, something that was (doi:10.1016/j.ccr.2011.05.026) largely overlooked for decades. The substantial parallels 11 Robinson JL, Macarthur S, Ross-Innes CS, Tilley WD, Neal DE, Mills IG & Carroll JS. Androgen receptor driven transcription in molecular between different hormonal cancers mean that insights apocrine breast cancer is mediated by FoxA1. EMBO Journal 2011 30 generated from one system (such as breast cancer) will 3019–3027 (doi:10.1038/emboj.2011.216)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/28/2021 09:01:49PM via free access European Journal of Endocrinology 29 28 27 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 Open Access Welboren WJ,van DrielMA,Janssen-MegensEM,vanHeeringenSJ, Lin CY, Vega VB,ThomsenJS,ZhangT, KongSL,XieM,ChiuKP, Carroll JS,MeyerCA,SongJ,LiW, GeistlingerTR,EeckhouteJ, Carroll JS,LiuXS,BrodskyAS,LiW, AJ,Eeckhoute MeyerCA,Szary Shang Y, HuX, DiRenzoJ,LazarMA&BrownM.Cofactordynamics Sewack GF&HansenU.Nucleosomepositioningandtranscription- Osborne CK,BardouV, HoppTA, ChamnessGC,HilsenbeckSG, Green KA&CarrollJS.Oestrogen-receptor-mediatedtranscription Glass CK&RosenfeldMG.Thecoregulatorexchangein Anzick SL,KononenJ,Walker RL,AzorsaDO,Tanner MM, Onate SA,Tsai SY, Tsai MJ&O'MalleyBW. Sequenceand Halachmi S,MardenE,MartinG,MacKayH,AbbondanzaC& Klinge CM.Estrogenreceptorinteractionwithestrogenresponse Merenbakh-Lamin K,Ben-BaruchN,Yeheskel A,DvirSoussan- Toy W, ShenY, Won H,GreenB,SakrRA,Will M,LiZ,GalaK, Robinson DR,Wu YM,Vats P, SuF, LonigroRJ,Cao X, Osborne CK&SchiffR.Mechanismsofendocrineresistance Musgrove EA&SutherlandRL.Biologicaldeterminantsof Sweep FC,SpanPN&StunnenbergHG. ChIP-SeqofERalphaand (doi:10.1371/journal.pgen.0030087) of estrogenreceptoralphabindingsites. Lipovich L,BarnettDH,StossiF 1289–1297. analysis ofestrogenreceptorbindingsites. Brodsky AS,KeetonEK,FertuckKC,HallGF (doi:10.1016/j.cell.2005.05.008) requiring theforkheadproteinFoxA1. mapping ofestrogenreceptorbindingrevealslong-rangeregulation J, ShaoW, Hestermann EV, GeistlingerTR 103 and sufficiencyinestrogenreceptor-regulatedtranscription. 31118–31129. pS2 promoter. associated chromatinalterationsonthehumanestrogen-responsive Institute tamoxifen resistanceinbreastcancer. estrogen receptorcoactivatorAIB1(SRC-3)andHER-2/neuin Fuqua SA,Wong J,AllredDC,ClarkGM&SchiffR.Role ofthe 2007 and theinfluenceofco-factorschromatinstate. 2000 transcriptional functionsofnuclearreceptors. Science steroid receptorcoactivatoramplifiedinbreastandovariancancer. Guan XY, SauterG,KallioniemiOP, Trent JM&MeltzerPS.AIB1,a 8674(00)80711-4) superfamily. characterization ofacoactivatorforthesteroidhormonereceptor (doi:10.1126/science.8197458) of hormone-inducedtranscription. Brown M.Estrogenreceptor-associatedproteins:possiblemediators nar/29.14.2905) elements. Cancer Research mechanism foracquiredendocrineresistanceinbreastcancer. et al Gutman L,JeselsohnR,Yelensky R,BrownM,MillerVA, SaridD hormone-resistant breastcancer. Fanning S,KingTA Genetics ESR1 mutationsinhormone-resistantmetastaticbreastcancer. Kalyana-Sundaram S,Wang R,NingY, HodgesL (doi:10.1146/annurev-med-070909-182917) in breastcancer. 631–643. endocrine resistanceinbreastcancer. . D538Gmutationinestrogenreceptor-alpha:Anovel 843–852. 7 14 1997 713–722. 2003 2013 121–141. (doi:10.1038/nrc2713) Nucleic AcidsResearch (doi:10.1038/ng1901) 277 Science 95 45 (doi:10.1016/S0092-8674(00)00188-4) (doi:10.1128/MCB.21.4.1404-1415.2001) Journal ofBiologicalChemistry Journal 2013

353–361. 1446–1451. 965–968. Annual ReviewofMedicine (doi:10.1016/j.fertnstert.2015.10.010)

(doi:10.1038/ni.3306) 1995 et al 73 . ESR1ligand-bindingdomainmutationsin 6856–6864. 270 (doi:10.1093/jnci/95.5.353) (doi:10.1126/science.277.5328.965) (doi:10.1038/ng.2823) 1354–1357.

2001

et al. Nature Genetics

Science

(doi:10.1038/ng.2822) Whole-genomecartography 29 Nature ReviewsCancer Journal oftheNationalCancer Journal J SCarroll Cell 2905–2919.

PLoS Genetics 2011 1994 et al 2005 (doi:10.1016/S0092- Nature Genetics 1997

et al . -wide Genes andDevelopment 2013 62 264 . Genome-wide et al 122 272 233–247.

1455–1458.

. Activating Nature Reviews 33–43. (doi:10.1093/ 2007

45

1439–1445. 2006

2009 3 Cell

e87.

Nature 38 2000

9

35 34 33 32 31 30 45 44 43 42 41 40 39 38 37 36 cancer ER generegulationinbreast Zwart W, TheodorouV, KokM,CanisiusS,LinnS&Carroll Kraus WL&KadonagaJT. p300andestrogenreceptorcooperatively Jozwik KM&CarrollJS.Pioneerfactorsinhormone-dependent Tan SK,LinZH,ChangCW, Varang V, ChngKR,PanYF, Magnani L,BallantyneEB,ZhangX&LupienM.PBX1genomic Eeckhoute J,KrasnickasKeetonE,LupienM,KrumSA,CarrollJS Hurtado A,HolmesKA,Ross-InnesCS, SchmidtD&CarrollJS. Cirillo LA,McPhersonCE,BossardP, StevensK,CherianS, Cirillo LA&ZaretKS.Anearlydevelopmentaltranscriptionfactor Cirillo LA,LinFR,CuestaI,FriedmanD,JarnikM& Laganiere J,DebloisG,LefebvreC,BatailleAR,RobertF&GiguereV. Li W, NotaniD,MaQ,Tanasa B,NunezE,ChenAY, MerkurjevD, Hah N,DankoCG,CoreL,Waterfall JJ,SiepelA,LisJT & Fullwood MJ,LiuMH,PanYF, LiuJ,XuH,MohamedYB,OrlovYL, Pan YF, Wansa KD,LiuMH,ZhaoB,HongSZ,Tan PY, LimKS, Dekker J,RippeK,M&KlecknerN.Capturingchromosome 4764–4776. transcriptional regulationofbreastcancer. JS. Oestrogenreceptor-co-factor-chromatinspecificityinthe srep20179) reinitiation. activate transcriptionviadifferentialenhancementofinitiationand nrc3263) cancers. emboj.2011.151) transcription. receptor-mediated long-rangechromatininteractionandgene Yong EL,SungWK&CheungE.AP-2gammaregulatesoestrogen pgen.1002368) breast cancer. pioneer functiondrivesERalphasignalingunderlyingprogressionin 6477–6483. receptor alphaexpressioninbreastcancer. looptiesGATA-3& BrownM.Positivecross-regulatory toestrogen EMBO Journal RNA polymeraseIIdefinesgenesdifferentiallyrespondingtoligands. (doi:10.1038/ng.730) and endocrineresponse. FOXA1 isakeydeterminantofestrogen receptorfunction (doi:10.1093/emboj/17.1.244) site onthenucleosome. winged-helix transcriptionfactorHNF3toalinkerhistone Shim EY, Clark KL,BurleySK&ZaretKS.Bindingofthe pone.0026217) free DNA. complex thatismorestableonnucleosomecoreparticlesthan Molecular Cell developmental transcriptionfactorsHNF3(FoxA)andGATA-4. Zaret KS.Openingofcompactedchromatinbyearly 102 that FOXA1definesadomainoftheestrogenresponse. Location analysisofestrogenreceptoralphatargetpromotersreveals 516–520. for oestrogen-dependenttranscriptionalactivation. Zhang J,OhgiK,SongX 622–634. response toestrogensignalinginbreastcancercells. Kraus WL.Arapid,extensive,andtransienttranscriptional human chromatininteractome. Velkov S,HoA,MeiPH 32977–32988. response elements. distal mediated longrangetranscriptionviaevolutionarilyconserved Bourque G,LiuET&CheungE.Regulationofestrogenreceptor- science.1067799) conformation. 11651–11656. Nature ReviewsCancer

(doi:10.1038/nature12210) (doi:10.1016/j.cell.2011.03.042) Molecular Cell

(doi:10.1038/emboj.2011.368) (doi:10.1158/0008-5472.CAN-07-0746) Genes andDevelopment 2009 2002 PLoS Genetics EMBO Journal (doi:10.1074/jbc.M802024200)

Science

(doi:10.1101/gr.4866006) Journal ofBiologicalChemistry Journal 28 9 279–289.

2002 1418–1428. 1999 et al EMBO Journal et al Nature Genetics 2011 Downloaded fromBioscientifica.com at09/28/202109:01:49PM 295 . Anoestrogen-receptor-alpha-bound 2011 . FunctionalrolesofenhancerRNAs 2012

4 (doi:10.1016/S1097-2765(02)00459-8) 961–969. 1306–1311. Nature 7 30 e1002368. 1998 (doi:10.1038/emboj.2009.88) 12

2569–2581. 1998 2009 381–385. 2011 12

(doi:10.1371/journal.

EMBO Journal Cancer Research 331–342. 175 17

(doi:10.1126/ 462

43 (doi:10.1371/journal. 244–254. www.eje-online.org :1 2008 27–33. 58–64. (doi:10.1038/ (doi:10.1038/

Nature

Cell

(doi:10.1038/ 283 PNAS

2011 2011

2007 2013

2005 145 30 R47

67 498

via freeaccess

Open Access J S Carroll ER gene regulation in breast 175:1 R48 cancer

46 Ross-Innes CS, Stark R, Teschendorff AE, Holmes KA, Ali HR, 62 Ghosh MG, Thompson DA & Weigel RJ. PDZK1 and GREB1 are Dunning MJ, Brown GD, Gojis O, Ellis IO, Green AR et al. estrogen-regulated genes expressed in hormone-responsive breast Differential oestrogen receptor binding is associated with clinical cancer. Cancer Research 2000 60 6367–6375. outcome in breast cancer. Nature 2012 481 389–393. (doi:10.1038/ 63 Smid M, Wang Y, Klijn JG, Sieuwerts AM, Zhang Y, Atkins D, nature10730) Martens JW & Foekens JA. Genes associated with breast cancer 47 Wolfrum C, Besser D, Luca E & Stoffel M. Insulin regulates the activity metastatic to bone. Journal of Clinical Oncology 2006 24 2261–2267. of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated (doi:10.1200/JCO.2005.03.8802) phosphorylation and nuclear/cytosolic localization. PNAS 2003 100 64 Davidson B, Stavnes HT, Holth A, Chen X, Yang Y, Shih Ie M & 11624–11629. (doi:10.1073/pnas.1931483100) Wang TL. Gene expression signatures differentiate ovarian/peritoneal 48 Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees serous carcinoma from breast carcinoma in effusions. Journal of CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al. Molecular Cellular and Molecular Medicine 2011 15 535–544. (doi:10.1111/j.1582- portraits of human breast tumours. Nature 2000 406 747–752. 4934.2010.01019.x) (doi:10.1038/35021093) 65 Hnatyszyn HJ, Liu M, Hilger A, Herbert L, Gomez-Fernandez CR, 49 Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Jorda M, Thomas D, Rae JM, El-Ashry D & Lippman ME. Correlation Johnsen H, Pesich R, Geisler S et al. Repeated observation of breast of GREB1 mRNA with protein expression in breast cancer: validation tumor subtypes in independent gene expression data sets. PNAS 2003 of a novel GREB1 monoclonal antibody. Breast Cancer Research and 100 8418–8423. (doi:10.1073/pnas.0932692100) Treatment 2010 122 371–380. (doi:10.1007/s10549-009-0584-x) 50 Kong SL, Li G, Loh SL, Sung WK & Liu ET. Cellular reprogramming 66 DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, by the conjoint action of ERalpha, FOXA1, and GATA3 to a ligand- Factor R, Matsen C, Milash BA, Nelson E et al. Tumor grafts derived inducible growth state. Molecular Systems Biology 2011 7 526. from women with breast cancer authentically reflect tumor (doi:10.1038/msb.2011.59) , growth, metastasis and disease outcomes. Nature Medicine 51 Serandour AA, Brown GD, Cohen JD & Carroll JS. Development 2011 17 1514–1520. (doi:10.1038/nm.2454) of an Illumina-based ChIP-exonuclease method provides insight 67 Zheng ZY, Bay BH, Aw SE & Lin VC. A novel antiestrogenic into FoxA1-DNA binding properties. Genome Biology 2013 14 R147. mechanism in progesterone receptor-transfected breast cancer cells. (doi:10.1186/gb-2013-14-12-r147) Journal of Biological Chemistry 2005 280 17480–17487. (doi:10.1007/ 52 Theodorou V, Stark R, Menon S & Carroll JS. GATA3 acts upstream s10549-007-9711-8) of FOXA1 in mediating ESR1 binding by shaping enhancer 68 Hickey TE, Robinson JL, Carroll JS & Tilley WD. Minireview: accessibility. Genome Research 2013 23 12–22. (doi:10.1101/ The androgen receptor in breast tissues: growth inhibitor, gr.139469.112) tumor suppressor, oncogene? Molecular Endocrinology 2012 26 53 Kouros-Mehr H, Slorach EM, Sternlicht MD & Werb Z. GATA-3 1252–1267. (doi:10.1210/me.2012-1107) maintains the differentiation of the luminal cell fate in the 69 Daniel AR, Gaviglio AL, Knutson TP, Ostrander JH, mammary gland. Cell 2006 127 1041–1055. (doi:10.1016/j. D'Assoro AB, Ravindranathan P, Peng Y, Raj GV, Yee D & cell.2006.09.048) Lange CA. Progesterone receptor-B enhances estrogen 54 Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, responsiveness of breast cancer cells via scaffolding PELP1- and Ewald AJ, Pai SY, Ho IC & Werb Z. GATA-3 links tumor differentiation estrogen receptor-containing transcription complexes. Oncogene and dissemination in a luminal breast cancer model. Cancer Cell 2008 2015 34 506–515. (doi:10.1038/onc.2013.579) 13 141–152. (doi:10.1016/j.ccr.2008.01.011) 70 Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, 55 Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Tarulli GA, Serandour AA, Birrell SN, Bruna A, Saadi A et al. Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, Progesterone receptor modulates ERalpha action in breast cancer. European Journal European of Endocrinology van der Wees J et al. Gata-3 is an essential regulator of mammary- Nature 2015 523 313–317. (doi:10.1038/nature14583) gland morphogenesis and luminal-cell differentiation. Nature Cell 71 Miranda TB, Voss TC, Sung MH, Baek S, John S, Hawkins M, Biology 2007 9 201–209. (doi:10.1038/ncb1530) Grontved L, Schiltz RL & Hager GL. Reprogramming the chromatin 56 Usary J, Llaca V, Karaca G, Presswala S, Karaca M, He X, Langerod landscape: interplay of the estrogen and glucocorticoid receptors A, Karesen R, Oh DS, Dressler LG et al. of GATA3 in at the genomic level. Cancer Research 2013 73 5130–5139. human breast tumors. Oncogene 2004 23 7669–7678. (doi:10.1038/ (doi:10.1158/0008-5472.CAN-13-0742) sj.onc.1207966) 72 Farmer P, Bonnefoi H, Becette V, Tubiana-Hulin M, Fumoleau P, 57 Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW, Van Tine BA, Larsimont D, Macgrogan G, Bergh J, Cameron D, Goldstein D et al. Hoog J, Goiffon RJ, Goldstein TC et al. Whole-genome analysis Identification of molecular apocrine breast tumours by microarray informs breast cancer response to aromatase inhibition. Nature 2012 analysis. Oncogene 2005 24 4660–4671. (doi:10.1038/sj.onc.1208561) 486 353–360. (doi:10.1038/nature11143) 73 Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C & 58 Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore Gerald WL. An estrogen receptor-negative breast cancer subset A, Zhang H, McLellan M, Yau C, Kandoth C et al. Comprehensive characterized by a hormonally regulated transcriptional program molecular portraits of invasive lobular breast cancer. Cell 2015 163 and response to androgen. Oncogene 2006 25 3994–4008. 506–519. (doi:10.1016/j.cell.2015.09.033) (doi:10.1038/sj.onc.1209415) 59 Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, 74 Pannuti F, Martoni A, Di Marco AR, Piana E, Saccani F, Khan AP, Quist MJ, Jing X, Lonigro RJ, Brenner JC et al. The Becchi G, Mattioli G, Barbanti F, Marra GA, Persiani W et al. mutational landscape of lethal castration-resistant prostate cancer. Prospective, randomized clinical trial of two different high Nature 2012 487 239–243. (doi:10.1038/nature11125) dosages of medroxyprogesterone acetate (MAP) in the treatment of 60 Brown AM, Jeltsch JM, Roberts M & Chambon P. Activation of metastatic breast cancer. European Journal of Cancer 1979 15 pS2 gene transcription is a primary response to estrogen in the 593–601. human breast cancer cell line MCF-7. PNAS 1984 81 6344–6348. 75 Alexieva-Figusch J, van Gilse HA, Hop WC, Phoa CH, (doi:10.1093/nar/15.4.1401) Blonk-van der Wijst J & Treurniet RE. Progestin therapy in 61 Berry M, Nunez AM & Chambon P. Estrogen-responsive element of advanced breast cancer: megestrol acetate – an evaluation of the human pS2 gene is an imperfectly palindromic sequence. PNAS 160 treated cases. Cancer 1980 46 2369–2372. (doi:10.1002/ 1989 86 1218–1222. (ISSN)1097-0142)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/28/2021 09:01:49PM via free access European Journal of Endocrinology 79 78 77 76 Open Access Birrell SN,RoderDM,HorsfallDJ,BentelJM&Tilley WD. Espie M.Megestrolacetateinadvancedbreastcarcinoma. Ingle JN,AhmannDL,GreenSJ,EdmonsonJH,CreaganET, Izuo M,IinoY&EndoK.Oralhigh-dosemedroxyprogesterone Medroxyprogesterone acetatetherapyinadvancedbreastcancer:the 1994 00062) Oncology women withadvancedbreastcancer. megestrol acetateversustamoxifeninparamenopausalorcastrated Hahn RG&RubinJ.Randomizedclinicaltrialof Treatment report ofclinicalandexperimentalstudies. acetate (MAP)intreatmentofadvancedbreastcancer. Apreliminary 51

(Supplement1)8–12. 1982 1981 5 1 155–160. 125–130. (doi:10.1007/BF01805865) (doi:10.1097/00000421-198204000- (doi:10.1159/000227408) J SCarroll American Journal ofClinicalAmerican Journal Breast CancerResearch and

Oncology

82 81 80 Accepted 15February2016 Revised versionreceived10February2016 Received 11August2015 cancer ER generegulationinbreast Bines J, Dienstmann R, Obadia RM, Branco LG, Quintella DC, Bines J,DienstmannR,ObadiaRM,BrancoLG,QuintellaDC, Muss HB,Wells HB,PascholdEH,BlackWR,CooperMR, Morgan LR.Megestrolacetatevtamoxifeninadvancedbreastcancer predictive valueofandrogenreceptorexpression. Annals ofOncology after nonsteroidalaromataseinhibitorfailure:aphaseIItrial. acetate inpostmenopausalwomenwithadvancedbreastcancer megestrol of Castro TM,CamachoPG,SoaresFA &CostaME.Activity Association. 5-year analysis Megestrol acetateversustamoxifeninadvancedbreastcancer: Capizzi RL,ChristianR,CruzJM,JacksonDV, PowellBL in postmenopausalpatients. Oncology 1995 Journal ofClinicalOncology Journal 13 – a phaseIIItrialofthePiedmontOncology 1572–1577. 2014 25 831–6. Downloaded fromBioscientifica.com at09/28/202109:01:49PM Seminars inOncology (doi:10.1093/annonc/mdu015) 1988 175 6 www.eje-online.org :1 1098–1106. 1985 Journal ofClinical Journal 12 43–47. et al

R49 . via freeaccess