Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 21 atrd rye mH Berlin/Boston. GmbH, Gruyter de Walter ©2017 Ray Amitabha of activator and [5]. transducer [3], are leptin pathways signal (MAPK), leptin-regulated (JAK), kinase of with protein kinase effects mitogen-activated associated Probably, Janus pathological and exist. e.g. (PI3K), and Ob-R molecules, 3-kinase physiological homeosta- phosphatidylinositol of signaling (STAT), both energy transcription isoforms intracellular in in six of important least number and is at A hormone Ob-Rb [4]. (Ob-R); suppressant) isoform receptors (appetite transmembrane leptin con- anorexigenic long through healthy an the functions pro- normal leptin as are In general, adipokines role leptin. In is these key sis. adipokines of a pro-inflammatory majority plays important the leptin the Nevertheless, dition, of organ. One endocrine nature. an in as inflammatory considered be can to tissue order pose in laboratories clinical in used are conditions. pathways health metabolic obesity-related and these different hormones of assess sex components of Many metabolism levels [2]. inflammation, systemic abnormal [1], low-grade in hyperinsulinemia, adipokines dysregulation dyslipidemia, chronic hyperglycemia, of a range e.g. wide observed, factors. mediates a obesity, been socioeconomic tissue In has and adipose processes. lifestyle disease excessive the genetic, an induces as possibly that which such agreed aspects cancers. generally multifactorial certain is with and it However, linked disorders and cardiovascular complex diabetes, highly 2 is type as such (BMI) diseases Organization of Health World number the a associated to According is of which obesity, is risk world the the throughout problems with health public important most the of one Currently Introduction Received: DOI: knowl- precise A tumors. acids. HER+ fatty against cells and Keywords: approaches leptin tumor obesity, therapeutic HER2+ as new such in of HER2 factors useful behavior several and is by the EGFR edge altered results, modulate be mixed can can shown levels leptin have HER2 and including studies IGF-1 insulin clinical Both like Although observed. characteristics pathways. commonly carcinogenesis, signaling are obesity-related IGF-1 In regulatory elevated metabolism. significant and play lipid which resistance or of pathways all lipogenic (mTOR), phosphatidylinosi- rapamycin (FASN), in of synthase roles target acid mechanistic of fatty and e.g. members (PI3K), AKT enzymes, three 3-kinase several other tol Further- with pathways. with connected signaling dimers intimately downstream activate is form can HER2 may and more, family it (EGFR) but receptor ligand, factor growth vitamin endogenous epidermal and known the health has no cardiovascular has HER2 preadipocytes, Conversely, HER2 of behavior. differentiation metabolism. tumor overexpressed as D aggressive is such indicates conditions HER2 presence normal general, in its In endothelial effects carcinomas; (HER2). certain vascular breast intracellular 2 (IGF-1), of the receptor factor-1 30% factor with growth roughly growth linked in insulin-like epidermal significantly as human and such (VEGF), factors factor adipokines of growth growth usually such types other are of certain of which one in pathways cytokines/adipokines, is increase signaling hormone-like Leptin an many nature. from releases in Apart tissue pro-inflammatory adipose one. well-studied excess obesity, obesity-related a Among in cancers. is lipids certain carcinoma including disorders breast health postmenopausal several of cancers, risk the with associated is Obesity 1 microenvironment lipid-related and obesity with association expression: HER2 Tumor-linked Ray Amitabha Article Review GRUYTER DE Abstract: aeEi olg fOtoahcMdcn,StnHl nvriy 0StnHl rv,Genbr,P 50,UA Phone: USA, 15601, PA Greensburg, Drive, Hill Seton 20 University, Hill Seton Medicine, Osteopathic of College Erie Lake (2)5228,Fx (2)5226,Emi:[email protected] E-mail: 552-2865, +(724) Fax: 552-2882, +(724) dps iseboyteie eea omn-iectknso dpkns[] nti ead h adi- the regard, this In [3]. adipokines or cytokines hormone-like several biosynthesizes tissue Adipose 10.1515/hmbci-2017-0020 ≥ 50 olwd n21;o hs 3 eeoee(BMI obese were 13% these of 2014; in worldwide 25.0] pi 4 2017; 24, April dps ise acr rB2 at cd,leptin acids, fatty ErbB-2, cancer, tissue, adipose stecrepnigauthor. corresponding the is 1 Accepted: etme ,2017 8, September ’ WO eot 9 faut eeoewih bd asindex mass [body overweight were adults of 39% report, (WHO) s omn oeua ilg n lnclIvsiain 07 20170020 2017; Investigation. Clinical and Biology Molecular Hormone ≥ 00.Teeilg foewih robesity or overweight of etiology The 30.0). 1 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd einllmhnd novmn,cepeso fteIF1rcpo IFR n GRwspeeti more in 2 present was EGFR with and signaling cases (IGF1R) cancer mitogenic receptor colorectal IGF-1 these of the study of of a the In coexpression Both and involvement, survival. with [22]. node IGF-1 and associated lymph proliferation gefitinib the be regional cellular between like to of crosstalk regulators inhibitors thought a potent are kinase are noticed pathways interactions have EGFR-tyrosine synergistic studies to Their of resistance [23]. number acquired a [22], time, [21], pathways long signaling a EGFR For ligands. its and (EGFR) role key a [20]. play [19], VEGF [18], like cancer elevated factors of as angiogenic pathogenesis such and the components leptin, in biological like several in- adipokines obesity, and in pro-inflammatory Finally, (IGFBPs), liver. IGF-1, the proteins bioavailable from IGF-binding pancreas IGF-1 in the of alterations condition, biosynthesis hyperinsulinemia, cannot this creased overcome cells causes To where which insulin. resistance [18], to insulin, insulin response proposed more of defective produces state been the a to has creates due explanation appropriately perhaps glucose obesity plausible utilize in a situation inflammatory cancers, The obesity-related [20]. of [19], pathogenesis the regarding ever, 1: Table and MDA-MB-361 in IGF-1 of [15]. expression cell-lines in cancer phosphorylation the breast Ob-R SK-BR-3 increased promoted and leptin IGF-1 BT474, with of MCF-7, MDA-MB-231, stimulation Alternatively, addition [14]. the cell-lines Moreover, that cancer [7]. breast showed IGF-1 SK-BR-3 animals liver-derived study experimental in the vitro increase In three-fold in the [13]. a an fat induced in control abdominal leptin IGF-1 the observed excess recombinant in in that of and higher administration IGF-1 report leptin was (mice) and another fat leptin by of visceral revealed of expression the were concentrations [8], in findings gene circulating [4], IGF-1 Similar higher increased [1], of [12]. expression an cases) 1) the cholecystectomy (Table detected while (non-obese [7] subjects group, group [6], obese human the [5], on of (IGF-1) fat study factor-1 subcutaneous A growth [11]. insulin-like and [10], (FGF21), [9], 21 factor growth fibroblast dpkn etn[] 1]Aioye;other Adipocytes; [11] [4], Leptin Adipokine growth Insulin-like resistance Insulin necrosis Tumor Inflammation (IL-6) Interleukin-6 growth or Cytokine Inflammation Category ieIF1 nte ieysuidgot tmltn opnn seiemlgot atrreceptor factor growth epidermal is component stimulating growth studied widely another IGF-1, Like How- [18]. [17], [16], diseases obesity-related or obesity and IGF-1 between relationship complex a is There (VEGF), factor growth endothelial vascular as such factors growth several with linked closely is Leptin Ray hr vriwo omnysuidctknsgot atr nobesity. in factors cytokines/growth studied commonly of overview short A [10] [1], (IGF-1) factor-1 [9] factor- [8] [1], factor α (TNF- α [1], ) epithelium mammary and gastric including cells body the throughout cells other Hepatocytes; cells (NK) killer natural and T-lymphocytes like cells other Macrophages; Function cells endothelial and fibroblasts, cells, immune as such types cell Many Receptor by produced Chiefly osignal to leads which gp130, transmembrane to binds complex ligand-receptor The sIL-6R. soluble and (gp80) IL-6R glycoprotein transmembrane the forms: Two bR forms Ob-Re soluble and Ob-Rb long the including isoforms 6 least At IL-6). for receptor (like family receptor cytokine I class the with Similarity receptor hybrid IR/IGF1R and (IR), receptor insulin the to also and (IGF1R), receptor its to bind can IGF-1 affinity higher cells, immune in mainly present TNFR-2: domain; death the possesses ubiquitous, TNFR-1: transduction metabolism of regulation and response, immune inflammation, on effect Pleiotropic balance energy in role key a plays normally and hormone, pleiotropic a like Acts properties autocrine and paracrine with along hormone, anabolic like Performs apoptosis and immunity inflammation, including Multifunctional EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd al 2: Table as such and (het- molecules D1 members intracellular cyclin of family (ERK), number kinase a other involve signal-regulated can with extracellular [50]. signaling transactivation [49], EGFR [48], [32]. through [47], HER2 [46], or including with [45], erodimerization) formation (homodimerization) [44], homodimer [43], a molecule [42], promoting [33]. [41], receptor by [32], [40], signaling another [39], 2) cellular [38], been initiate (Table have [37], may ligands which [36], EGFR ligands, [35], several ligand-induced corresponding [34], Nevertheless, by of 2 Table activated role re- the biological be factor in the can briefly on growth shown EGFR depends studied however, receptors homolog individual commonly HER2; of oncogene for are function derived ligand The (c-erbB-2)] neuro/glioblastoma no 2 or is oncoprotein There HER2 leukemia ceptors. and erythroblastic EGFR cellular growth (HER1-4), [or epidermal family (neu) human Among this activity. or kinase of (ErbB) tyrosine members possess B glycoproteins, four homolog transmembrane are oncogene which family, viral (HER) leukemia receptor factor erythroblastic or EGFR of Members family its and EGFR The of one as crosstalk EGFR IGF1R promotion. and phosphorylated tumor IGF1R enhanced of the obesity expression documented from for with [31] high originating mechanisms al. tissues with potential et metastases (NSCLC) cases the Moore brain in Furthermore, cancer In [30]. recorded lung mutations was expression. cell EGFR survival and IGF1R non-small median of most shorter a levels that cancer, high found lung [25], [29] associated prognosis high al. poor had with with overexpression et cases correlated cancer, Morgillo EGFR were study, pancreatic EGFR another in of Interestingly, In detection [28]. cytoplasmic [26]. [27], and such [26], IGF1R cancers [25], of other in expression cancer demonstrated membrane breast been has and crosstalk cancer IGF1R and pancreatic EGFR as the Moreover, [24]. tumors of 75% than GRUYTER DE 12q13 ErbB3 17q12 HER2 description Brief 7p11.2 Ligands EGFR Members a a a h rBfml eetr n soitdligands. associated and receptors family ErbB The eeui HG tutrlysmlrt R,HGcnit ffu sfrs R14 HRG HRG1-4. isoforms: four of consists HRG NRG, to similar Structurally of important). member are a (HRG) 2 MUC4, Heregulin and with NRG1 complex ErbB3, a (for form NRG1-4 may members: HER2 four that has hypothesized family effect, is The mitogenic It potent has It actions. biological similar has epigen EGF, Like (NRG) Neuregulin as well as angiogenesis, and proliferation cellular in part MUC4 takes ? Epiregulin Epigen functions biological Its cells. of variety wide a by expressed is Betacellulin Epiregulin plays HB-EGF monocytes/macrophages. in detected is HB-EGF of Expression Betacellulin cells, epithelial as such cells of number a by produced HB-EGF is Amphiregulin Amphiregulin (TGF- factor- growth Transforming (EGF) factor growth Epidermal α ) α R sipiae nvroscnes[8,[9,[50] [49], [48], cancers various of in activity Abnormal implicated and systems. is development nervous HRG the and cardiovascular in role the of necessary maintenance a plays and growth, cellular affects [47] [46], [45], schizophrenia and cancer as different such in involved conditions is disease it Moreover, development. system cardiovascular and I types isoforms: six includes NRG1 number a in documented been [44] has carcinomas glycoprotein of this of expression aberrant An IFN- like Cytokines family. mucin [43] weaker is affinity binding its though neoplastic in involved also is [42] It [41], healing. wound process and repair tissue like conditions [40] [39], prognosis with in associated overexpressed and is cancers It different formation. myelin and neurogenesis of promotion pancreatic of differentiation include [38] the receptor as toxin acts diphtheria also heart It healing, tumorigenesis. wound atherosclerosis, e.g. adipogenesis, development, processes, biological various in roles significant [37] cancer development, and gland biological inflammation several mammary in proliferation, implicated keratinocyte been e.g. has phenomena, It cells. immune and fibroblasts [36] [35], hyperplasia mucosal gastric TGF- addition, In cases. Like keratinocytes. and macrophages including EGF cells various in expressed is [34] It growth growth neoplastic the certain the in in of role documented Dysregulation key cells. a various plays of and proliferation manner paracrine and or autocrine as functions It the , TGF- α eei novdi eea acr n oecetlip/palate cleft some and cancers several in involved is gene α β sascae ihMntirdsae iodrof disorder a disease, Ménétrier with associated is ctnn[51]. -catenin γ n TGF- and – β I R1pasvtlrl ntenervous the in role vital plays NRG1 VI. cls mloaino hyperglycemia, of amelioration -cells, β lorglt U4expression. MUC4 regulate also EGF eehsbeen has gene Ray 3 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 4 factor. risk a as considered is obesity where pathologies 3: Table abovementioned the vivo in in modulated and be vitro could in [91]. EGFR different [90], However, that [81], intricate. revealed [94]). [80], is [93], subjects [79], [92], environment circumstances human [32], lipogenic on 5 the studies (Table and in group expression experiments EGFR sensitive EGFR tamoxifen of pathogene- and to status obesity, the cancer compared with the in breast cases associated Overall, postmenopausal EGFR was resistance tamoxifen of 100 resistance tamoxifen in analyzing role that higher after detrimental found was study, the [91] clinical recorded al. ApoE a has et (using In Xuan [89]) study specimens, [90]. [88], vivo nephropathy [87], in obesity-related tyro- [86], et of recent [85], receptor Pagano sis A [84], stimulate cells, HER2. [83], and 3T3-L1 [82], and heterodimerization 4 same EGFR EGFR-HER2 Table the both the of using induce shown was phosphorylation addition, can EGF sine EGF In hand, that [80]. other demonstrated the preadipocytes On [81] 3T3-L1 [79]. al. mediators in related proliferation other stimulate or (EGF) to factor growth (an epidermal con- cell-line acid endothelial ligand oleic the ECV-304 by the in Nevertheless, activated Nor- study be [78]. vitro [77]). could in processes EGFR [76], One that neoplastic [75], complicated. showed [74], is in EGFR [73], (DMs) and [72], lipids/adiposity minutes [71], between double nection [70], like [69], elements [68], [67], DNA [66], chromosomal [65], [64], [63], [62], the mally, [61], [60], [59], [58], [57], HER2/ErbB3 including receptors family ErbB other the of subunits as act receptors two These heterodimers. domain. kinase defective a has a hoooa oain BEF eai-idn G-iegot atr IFN- factor; growth EGF-like heparin-binding HB-EGF, location. Chromosomal organs reproductive Female Speci- tract Digestive site Cancer system Body 2q34 ErbB4 h rsneo GRi eetdi ierneo acrtps(al 5] 5] 5] 5] 5] [56], [55], [54], [53], [52], [51], 3 (Table types cancer of range wide a in detected is EGFR of presence The a Ray idnso eetv tde nimnhsohmclepeso fEF n E2i ieetcne ye or types cancer different in HER2 and EGFR of expression immunohistochemical on studies selective of Findings EGFR eeui R14(icse above) (discussed HRG1-4 above) (discussed NRG1-4 Epiregulin Betacellulin HB-EGF Heregulin Neuregulin eei oae ncrmsm .Hwvr the However, 7. chromosome on located is gene aces3 04. GRadHER2 and EGFR 41.7 4 50 74 36 50 Pancreas Gallbladder (adenocarcinoma) Esophagogastric (adenocarcinoma) Esophagogastric (adenocarcinoma) Esophagogastric noeru 42. 82EF a linked was EGFR 88.2 associated was EGFR 77 23.5 2 34 43 1 1 63 86 32 associated was EGFR 91 66.7 44 Endometrium 127 (postmenopausal) 50 Breast 72 (postmenopausal) Breast 36 Colon Colon Colon Pancreas Pancreas – – – icse above discussed above discussed above discussed analyzed mens 551 18 13 1515 3 949 49 135 15 27 293 amplification EGFR 14.1 32.7 220 27 40 73 52 ω EGFR+ 9ftyai)idpneto n uorn erto of secretion autocrine any of independent acid) fatty -9 cases, % HER2+ EGFR γ cases, interferon- , % eecudb soitdwt h extra- the with associated be could gene progression disease with – – prognosis poor with – – – metastasis with stage clinical to related were – – – body gastric than junction gastro-esophageal near tumors in common Investigators more was Comments γ E2hsn nw iad n ErbB3 and ligand; known no has HER2 . − / − n 5B/ mice, C57BL/6 and age l [64] al. et Wang [63] al. et Ray [62] al. et Knoop [61] al. et Khelwatty [60] al. et Takahari [59] al. et Leung [58] al. et Walsh [57] al. et Pryczynicz [56] Yuan and Zhang [55] al. et Doval [54] al. et Fuse [53] al. et Chan [52] al. et Birkman EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd al 4: Table a GRUYTER DE iie riaeut vdnefrteascainbtenoeiyadcne ik[77]. risk cancer and obesity between association the for evidence inadequate or Limited cells: cancer Experimental Ovarian human Origin: Esophageal cells: cancer Breast digestive Upper system Reproductive human Origin: cell-lines Cancer models vitro In types cancer Other OVCAR-3 T47D [83] cells: [82], cancer SK-BR-3 Gastric MDA-MB-468 MDA-MB-453 MDA-MB-435s [83] MDA-MB-361 MDA-MB-231 MCF-7 [83] [82], BT474 eeati ir n nvv xeietlmdl ncneto ihHR overexpression. HER2 with connection in models experimental vivo in and vitro in Relevant a vr 41 11 19 impacted HER2 64 41.3 correlated EGFR 59 39.7 63 49 69 Ovary Endometrium Endometrium cells: adenocarcinoma system 83 71 60 42.2 Androgen- 53.3 72 24 23 22.4 45 62.7 3 43 30 16 had HER2+ bladder 67 Urinary 45.1 106 12 21 bladder tumor Urinary on 18.3 Depending bladder Urinary 35 130 42 82 bladder Urinary 62 25.2 Prostate 28.5 783 breast Male breast 123 Male Ovary Ovary Ovary cells: cancer Pancreatic FLO BIC-1 xC3Preadipocytes/adipocytes: Capan-1 BxPC-3 MKN74 MKN28 [86] OE33 [86] [85], OE19 cells: Endothelial cells: cancer Colon system digestive Lower C16Rtmodels Rat SW613 epithelial Mammary SW480 [88] LS174T LoVo (embryonic) Kidney HT-29 HCT116 FET DLD-1 DiFi [88] Caco-2 disease) fibrocystic from cells: cells: cell-lines non-tumorigenic Normal/ 3T3-L1 (derived MCF10A HBL100 184.a1 HEK293T ECV-304 – – – – disease independent – – behavior aggressive risk mortality increased HER2+ grade, – – prognosis survival and metastasis with rats mice transgenic [89] mice transgenic HER2/neu models Mouse animals models vivo In itrrats Wistar Sprague-Dawley MMTV/v-Ha-ras or MMTV-neu mice C57BL/6 ApoE [76] al. et Carlsson [75] al. et Enache [51] al. et Naik [74] al. et Kiyoshima [73] al. et Hernes [72] al. et Kornegoor [71] al. et Ge [70] al. et Demir [69] al. et Nielsen [68] al. et Ali-Fehmi [67] al. et Goff [66] al. et Mori [65] al. et Khalifa − / − mice Ray 5 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 6 1). (Figure conditions disease and normal significantly both alter com- in could is pathways types signaling cell it EGFR different Therefore, and of isoprostanes. leptin behavior product adipokine the between peroxidation crosstalk tis- lipid the in of that ERK excretion prehended increased and urinary by kinase accompanied and was tyrosine hyperleptinemia concentration experimental c-Src this plasma with Furthermore, [98]. along kidney and EGFR aorta of like sues phosphorylation EGF- increased heparin-binding leptin EGFR-ligands of factor- of administration growth transforming expression and and BIC-1 gene (HB-EGF) OE19, factor increased OE33, growth of like via proliferation cells the adenocarcinoma stimulate to esophageal shown MCF-7 FLO was and leptin MDA-MB-231, Alternatively, MDA-MB-468, [96]. in cells that found EGFR cancer was transactivated breast way, it synergistically same the cotreatment In IGF-1 [95]. cell-lines and cancer leptin gastric MKN74 and MKN28 in EGFR of phosphorylation 5: Table HER2. express commonly cells all although expression, HER2 higher indicates number(s) reference with model Cell-line/experimental aaii 3] 9]Da tyrosine Dual [92] [32], Lapatinib [92] [32], Cetuximab [94] emtansine Ado-trastuzumab Monoclonal [94] Trastuzumab estrogen Selective [93] Tamoxifen kinase Tyrosine [92] [32], Gefitinib agents Therapeutic eea tde aeosre htlpi a tmlt GRsgaig etnidcdsgicn tyrosine significant induced Leptin signaling. EGFR stimulate can leptin that observed have studies Several UL-1 [84] SK-OV-3 Ray eetv agtdtetetmdlte ncne ihrfrnet EGFR/HER2. to reference with cancer in modalities treatment targeted Selective iaeinhibitor kinase inhibitor antibody Monoclonal conjugate Antibody-drug inhibitor antibody (SERM) modulator receptor inhibitor properties Pharmacological

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(tumors HER2 cells cancer HER2-positive targets agent This prevent ER to estrogens of activation endogenous the with competes It express (ER). that receptor tumors estrogen i.e. cancer, breast its hormone-sensitive blocks for and transduction Treatment EGFR signal of cellular domain inhibits kinase which tyrosine phosphorylation, the for competes drug This cells/biomolecules Targeted α α (TGF- cells epithelial mammary cells ovary hamster α MM:Mouse NMuMG: Chinese CHO: 9] na nvv td i itrrats), Wistar (in study vivo in an In [97]. ) EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd n rB eetr nbt er n iny 14.I eea,ti os oe spoet eeo disor- develop to prone is prevented model treatment mouse neuregulin-1 this However, nephropathy. general, and In [114]. atherosclerosis, cardiomyopathy, kidneys as and such HER2 heart of ders both activation systemic in (ApoE induce receptors mice to ErbB4 demonstrated diabetes and been 1 has streptozotocin) type recombi- by E-deficient induced of hyperglycemia apolipoprotein Administration mice, hypercholesterolemic [113]. 2) in Table neuregulin-1 factor, growth human EGF-like nant (an neuregulin-1 by mediated are the ocardium heart with the associated of 5). be (Table development could blockade the trastuzumab HER2 in the with toxi- of roles treatment effects cardiac Therefore, physiological deleterious of [112]. important [108], [111], risk plays therapy survival the HER2 cardiomyocyte antibody) increase that and monoclonal might shows (HER2-targeted trastuzumab obesity Evidence received that the [110]. who in indicated [109], patients release have its cancer studies after breast hand, measured various in be other city with can the which HER2 domain, On circulating extracellular stream. the of blood from derived association is (HbA abnor- positive HER2 hemoglobin with a glycated circulating associated note, and observed triglycerides, frequently BMI, study hyperglycemia, are e.g. a pathologies parameters, Interestingly, obesity-related these leptin. syndrome: of metabolic levels and mal diabetes 2 type obesity, as cell-line. between pathways. interactions signaling epithelial intracellular the Possibly, mammary different HER2. involving human and bidirectional MCF10A leptin are between leptin in cooperation and leptin close HER2 showed a of [106] indicate al. activation et examples Cha transcriptional two contrast, These In induce [105]. wall can arterial the HER2 in [104]. activity that [103], HER2 increase obesity to in documented precursor been pathologies has from metabolic mia adipocytes with linked mature is of possibly development regarding process the instance, this of in For preadipocytes process impairment tissue. of and intricate differentiation adipose cells, the an of during is Research role activities Adipogenesis androgens. a have [102]. metabolic from might (3T3-L1) HER2 estrogens other that of to hypothesized predominant been synthesis connected the has the it also of adipogenesis, catalyzes that one is enzyme noticed whose HER2 this [101] aromatase that and al. of suggests tissue et activity adipose Subbaramaiah hormone-dependent increased in proliferation. In is with cellular [100]. locations associated the cells was stimulate cancer HER2 can and estrogen of proliferation, normal overexpression cell that as in known such is both functions, it transduction, cellular cells, signal of variety and a repair, regulate the damage in and HER2 DNA nucleus including the in proteins and to ErbB regions structures the translocate localized raft that can both patchy suggested membrane alter been are can has which cholesterol it Interestingly, rafts, membrane [99]. pathways Thus, lipid signaling signaling. with HER2 cell associated in involved be and to membrane found cell been the have HER2 and EGFR Both expression HER2 of Characteristics conditions. pathological and normal both in events cellular different in involvement their 1: Figure GRUYTER DE ietecripoetv ffcso E2 ada eeomn n eea uvvleet ntemy- the in events survival several and development cardiac HER2, of effects cardioprotective the Like such conditions by accelerated be can sequelae its and atherosclerosis like events cardiovascular Different hyperleptine- and expressed; abundantly are HER2 and EGFR both system, cardiovascular the Throughout neatosaogvrositaellrsgaigmlcls hc r once ihEF n bR and Ob-R, and EGFR with connected are which molecules, signaling intracellular various among Interactions 1c 17.Of [107]. ) Ray − / − 7 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 8 induced leptin acid that arachidonic reported [137] with al. et associated Soma is hand, COX-2 other the isoform On inducible conditions. VEGF, pro-inflammatory the factor and note, angiogenic metabolism PI3K, Of molecule [14]. transduction (COX-2) signal cyclooxygenase-2 as and such proteins cellular various increase to shown HER2. no to in- less The express [136]. which MDA-MB-435s [135], MDA-MB-231, cell-lines, with cells MCF10A along cancer cell-lines, and SK-BR-3 breast and HER2+ BT474 in HER2-expressing FASN high upregulated used and vestigators saturation, acid cell-line both fatty HER2, higher epithelial contents, and mammary FASN human between HER2( connection of to comparison intimate long- transfection Astonishingly, of an the other. formation is with the each there HBL100 catalyzes regulate that which positively appears (FASN), It which synthase [133]. acid of [132], fatty acids of of fatty inhibition downregulation SK-OV-3, by chain BT474, SK-BR-3, and recorded in expression), been i.e. (low cell-lines, has MCF-7 cancer HER2 ovarian expression), and HER2 breast (moderate HER+ different T47D MDA-MB-453, In metabolism. acid fatty and HER2 ( acid [130]. AKT of as trastuzumab- phosphorylation reduced rapid significantly stimulated and adipocytes cells differentiated HER2+ from of media inhibition conditioned growth mediated in cells cancer note, breast Of 3 [129]. patients from cancer breast cells postmenopausal tumor ER obese mammary possibly from and serum cells with SK-BR-3 (ER incubation HER2+ beta after in mice documented receptor MMTV-neu were estrogen Bcl-2 protein of anti-apoptotic suppression and study, D1 vitro in an In observations vivo in and vitro in obesity: in HER2 and cancer Breast and HER2 exploit likely most cells Tumor progression. embry- life. cancer the and our survival in throughout continued development function their heart for from cardiac pathways starting myocardium of associated roles the maintenance fundamental in to plays pathways HER2 state survival fact, onic In several Interestingly, HER2. by metabolism. [128]. mediated [127], vitamin are [126], in [125], participation [124], metabolism and calcium effect, vitamin and this tissue of bone functions of the maintenance that indicates the clearly to evidence obesity limited Recent It and not [123]. deficiency D. are leptin D vitamin including vitamin cytokines between of tissue association role adipose the complex several on ad- regulates highly Interestingly, increased D a vitamin calcitriol D1. suggests that that noteworthy cyclin evidence documented is accumulating and has study Therefore, AKT level. the in ERK, addition, expression protein HER2 In as neuregulin-1 promote [122]. such to rats of demonstrated Sprague-Dawley pathway activation been of signaling has myocardium the (calcitriol) study,the its decreased D this vitamin of and In active levels hormonally tumors, [121]. of protein mammary efficacy ministration another as therapeutic of Conversely, well its development group. than as the rather delayed treatment HER2 analog only BXL0124 same treatment the the BXL0124 of in vitamin the in role multiplicity Gemini preventive decrease tumor the 50% the recorded and than that study the more weight observed were regulating tumor There through [120] growth, mice. tumors al. transgenic tumor mammary MMTV-neu et HER2-overexpressing in character- of Lee pathways derivatives, growth signaling (Gemini). D HER2/AKT/ERK the carbon-20 vitamin inhibited to (BXL0124) synthetic analog attached with from D obtained treated side-chains were were two results which by Similar mice, [119]. ized transgenic [118], MMTV-neu patients cancer in breast studies HER2+ among prognosis in provement HER2 of homolog rat the of adenocarcinomas. form but mammary positive activated spontaneous HER2 expresses develops are model and cells mouse SK-BR-3 transgenic that (MMTV)-neu and noting virus mRNA worth tumor is HER2 mary It HER2/neu both (ER [117]. and tumors negative reduced in cells receptor tocotrienols as cancer estrogen well isomers as breast E SK-BR-3 cell-line tissue mi- cancer vitamin in in the these of study protein strongly of supplementation a impact many In mice, and Furthermore, [116]. female tissue [115]. [20], transgenic adipose inflammation properties in and anti-cancer genes homeostasis, have several energy cronutrients regulate adipogenesis, vitamins as These such E. biology and D A, tamins pathologies. renal along the size, of plaque atherosclerotic alleviation reduced with and function, contractile LV improved dilatation, (LV) ventricular left α h diino etnt E2 D-B31(R)adS-R3(ER SK-BR-3 and (ER+) MDA-MB-361 HER2+ to leptin of addition The such acids fatty dietary that showed [131] al. et Menendez cell-lines, SK-BR-3 and BT474 using study a In cardioprotective adipogenesis, of regulation as such roles physiological of number a has HER2 Overall, im- significant with associated be to shown been also has supplementation D vitamin tocotrienols, Like vi- as such vitamins fat-soluble including micronutrients several for reservoir major the is tissue Adipose lnlncai ( acid -linolenic ω Ray 6 nrae E2etaellrdmi ocnrto.Pras hr sacoeascainbetween association close a is there Perhaps, concentration. domain extracellular HER2 increased -6) β xrsini orltdwt etrponss eetees utr fHR+B44adSK-BR- and BT474 HER2+ of culture Nevertheless, prognosis. better with correlated is expression FASN ω 3ftyai) ioaeteocai ( acid eicosapentaenoic acid), fatty -3 − ratcne el,suisfudamtblclydffrn iuto uha oe lipid lower as such situation different metabolically a found studies cells, cancer breast ) eesgicnl nrae xrsinlvl fEF n E2poen 14.In [134]. proteins HER2 and EGFR of levels expression increased significantly gene − ua rataeoacnm elln;wieHR/e rmuemam- mouse or HER2/neu while cell-line; adenocarcinoma breast human ) ω 3,adoecai ( acid oleic and -3), β xrsinadhge xrsino cyclin of expression higher and expression ) ω − 9 oneuae u linoleic but downregulated -9) ratcne ellnswas cell-lines cancer breast ) EGRUYTER DE ’ s Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd E2lmnllk HR+ R n/rP+.Teeaeas oels omnyue rus ..molec- e.g. groups, used commonly less or some B/HER2+ also are luminal There and ER PR+). normal-like (HER2+, and/or as HER2-enriched ER+ into such and (HER2+, categorized groupings negative HER2/luminal-like are triple additional tumors B, make general, A, frequently In luminal investigators HER2. However, i.e. and subtypes, PR, ER, molecular as main such four distant markers of prognostic of incidence expression cumulative chemical and survival overall worse with correlated ER in significantly ER metastases with obesity and [153], grade al. advanced tumors, et larger (PR with correlated negative was genereceptor obesity that (FTO) noteworthy that obesity-associated is noticed It and [152] higher. mass al. significantly fat was perplexing the cancer breast is that of the recorded cancer subtype [151] HER2-overexpressed breast al. the HER2-overexpressing in et and Tan expression obesity Nonetheless, between [150]. [149], association [148], the condition, clinical In obesity to reference with HER2 and cancer breast on studies Clinical and tissues. promoter lymphoid MMTV and salivary the as of such control sites v-Ha-ras other the transgenic in under the growth oncogene that neoplastic mentioning ras with worth along the is tumors expresses high-fat It mammary background develops [147]. with FVB incidence comparison levels tumor of RNA in in model decreased reduction diet restriction mouse food a oil mice, HER2 with transgenic olive along MMTV/v-Ha-ras of in high-fat HER2, study of decrease by another In pathway a [146]. transduction diet 7,12-dimethylbenz[a]an- reported oil signal of corn rats study relevant Sprague-Dawley A the models. in and experimental vivo tumorigenesis mRNA in mammary other (DMBA)-induced in HER2 thracene of levels expression the alter IGF-1. and insulin estradiol, leptin, of mRNA levels ER both ER serum mammary group, of restriction in levels and caloric In increase protein diet) [145]. low-fat and an regimen (high-carbohydrate, overweight diet) elicited high-fat with (high-carbohydrate, restriction comparison obesity caloric in diet-induced unaffected mice was that transgenic rate shown MMTV-neu fatty growth in has tumor a pression but report that appearance observed recent tumor model delayed A mouse and transgenic [144]. incidence this tumor on reduced study reduced diet intervention drastically acid-free dietary acid Another eicosapentaenoic of levels. consumption leptin Furthermore, serum [143]. (87%) group a control eicosapen- and of ad-libitum tumor consumption a second and mice, ( a restriction MMTV-neu of calorie acid Among onset intermittent [142]. taenoic tumor earlier combined tumors first that multiple an a found of had study of number diet intervention onset absolute high-fat dietary of greater a time a on and the mice incidence though altered, study, leptin greater not twofold subsequent serum were a However, rates In [141]. growth group. groups tumor mice all and diet de- for high-fat cancer similar in for were higher were period were burden mice latency levels tumor obesity-prone although and of groups; weights metastasis control body incidence, diet final velopment, low-fat mice, and MMTV-neu obesity-resistant in to obesity compared diet-induced heaviest on study initial an In experiments vivo in of Results HER2 between found was relationship a associa- Likewise, close a synthesis. recorded acid studies fatty of leptin. catalyzes number and that A FASN levels. with HER2 HER2 cellular of on impact tion post- way, differ- an same obese showed the acids from In fatty adipocytes. serum dietary differentiated with ent from media incubation conditioned after or patients behavior cancer aggressive breast menopausal exhibited which SK-BR-3, is cell-line cancer breast [138], to cells leptin HER2-overexpressing of Further- especially administration cell-lines), used. human the MCF-7/HER2 were [140]. normal after and (NMuMG) study, tamoxifen MCF-7, this cells (MDA-MB-231, antiestrogen In epithelial cells to [139]. cancer sensitivity mammary leptin reduced mouse to found normal response studies cells. and greater more, MCF-7/HER2-18 line) and transfected (184.a1 Ob-R stably epithelium of in breast reported expression as were mRNA well cells high as epithelial exhibit mammary to cells treat- SK-BR-3 HER2-transformed leptin transformation, that in revealed oncogenic [138] levels following al. Conversely, protein et Giordano HER2 addition, increased In cells. ment SK-BR-3 in HER2 of phosphorylation tyrosine GRUYTER DE osdrn h lnclueuns,bes uosaeuulycasfidacrigt h immunohisto- the to according classified usually are tumors breast usefulness, clinical the Considering to shown been have also interventions dietary mice, transgenic MMTV-neu abovementioned the from Apart breast HER2+ studied commonly A receptors. HER2 of levels varied express cells cancer breast Different FTO eei oae ncrmsm 6 n a ls ikwt M.O h te ad oger et Bouguerra hand, other the On BMI. with link close a has and 16, chromosome on located is gene ω 3ftyai)sgicnl eue h amr uo niec 1% ncmaio with comparison in (15%) incidence tumor mammary the reduced significantly acid) fatty -3 − HR+bes cancer. breast /HER2+ − ,adHR+bes acrsbye iial,i td odce yMazzarella by conducted study a in Similarly, subtype. cancer breast HER2+ and ), α n ER and β eeicesd nadto,mc nteclrersrce ithdlower had diet calorie-restricted the on mice addition, In increased. were − α progesterone , − n ER and n PR and Ray β − ex- ). 9 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 10 as such mechanisms several via progression tumor promotes and the mediator induced lipid PGE2 pathway. acid pro-inflammatory signaling arachidonic known HER2/ErbB3 the a the through is (PGE2) that E2 motility reported prostaglandin and of [163] accumulation adhesion and al. and COX-2 survival, of et 2); proliferation, expression Vadlamudi (Figure the Furthermore, in frequently [164]. involved occurs cells kinase dimerization tumor lipid protein) of a kinase-defective that PI3K, (a considered activate ErbB3 is can heterodimeric heterodimer It and formed this receptor) cells. HER3) orphan cancer (or colorectal (an ErbB3 in HER2 and between residues HER2 tyrosine SW480, that the phosphorylated Caco-2, LS174T, demonstrated of and DiFi, They activation e.g. complexes FET. and cell-lines, and carcinoma expression colorectal HCT116 the human SW613, examined of HT-29, [163] number al. a prolif- in et decreased Vadlamudi members with family and cells. associated EGFR PI3K of was apoptosis molecules phenomenon increased transduction This and signal silenced. was eration intracellular HER2 and FASN when downregulated of were expression differentiation. AKT enterocytic that in of FASN observed characteristics and they exhibits HER2 addition, that of levels cell-line In expression adenocarcinoma elevated colon recorded human [162] a al. cells, et Caco-2 Li worldwide. mortality of causes leading classification TNM involvement, modified node (a lymph staging invasion, (AJCC) gastric Cancer tumor lep- on in of of Committee system). depth HER2 Joint expression the American the and the with gastric between and Ob-Rb associated correlation normal expression significantly leptin, VEGF a of were of was both specimens angiogenesis. there levels HER2; Moreover, 96 and expression and mucosa. with tin motility higher normal along to cell significantly specimens compared found proliferation, tissues cancer [161] cellular cancer gastric al. as 110 et such analyzing Geng functions after mucosa, of hand, range mediators other sphingosine wide lipid the It active a On biologically [160]. and in are well-differentiated involved cells 1-phosphate acid are adenocarcinoma sphingosine cell-lines, and tubular that cancer acid lysophosphatidic MKN74 lysophosphatidic gastric differentiated that human lysophospholipids, noteworthy moderately is two and principal in cells HER2 adenocarcinoma two of MKN28 phosphorylation that induced demonstrated 1-phosphate, study A system digestive the of diseases Malignant expression HER2 and organs other of Tumors peroxidation lipid against protect to breast cells of cancer group for HER+ beneficial survival. the be their in might and found worth HER2 were of is years, (SOD) Overexpression lipids dismutase It [159]. 10 and of (MDA) superoxide cancer presence malondialdehyde cases. of enzyme product the peroxidation antioxidant span cancer by lipid of characterized a of breast levels levels and Over decreased 3206 increased cancer study, interesting [158]. breast of an of ER In out type cells. for rare the carcinoma a negative in is lipid-rich were carcinoma with cases lipid-rich that all patients mentioning and 49 PR detected for investigators positive the were the 10.2% in only higher whereas significantly was FASN of expression tissue posi- The [157]. HER2 1 of subtype. oxidase HER2 association acyl-CoA on an study and revealed FASN a cancer hand, with breast other these tivity the metastatic though On fractions, in cancer. lipid breast proteins/enzymes in blood metabolism-related expression relevant lipid HER2 of with levels significantly altered correlate similarly not observed did controls parameters [156] lean al. than et cases Jain cancer Likewise, breast among [155]. recorded were levels elevated not HDL-cholesterol com- significantly was decreased parameters, patients controls and triglycerides lean syndrome-related cancer and metabolic breast overweight/obese between regarding of levels Nonetheless, leukocytes mRNA significant. of in statistically difference levels the mRNA samples, But, HER2 blood controls. in lean higher biomarkers to significantly transcriptional pared found of analysis [155] After al. subtypes. post- tu- et molecular any in HER2+ Alokail were of (HDL)-cholesterol and subtype risk lipoprotein the resistance high-density cancer to and insulin related triglycerides breast between not of HER2+ levels association blood study, with an this associated documented in However, mors. also significantly waist the study be that Their to observed women. 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HEK293T cancer and ovarian cells of fluid (CHO) ascitic the from derived lipids dia- like HER2 conditions obesity-related [176]. and risk [175], use [174], the tobacco [173], in as [172], similarities clinical syndrome such many metabolic cancers and are and bladder pattern there betes Fascinatingly, urinary expression [171]. and as cancers pancreatic such Wilm of pediatric HER2 factors including in of cancers different features are pediatric several various perhaps cancers, outcome in adult It reported with [170]. been 20% comparison has below in frequencies however, expression had fre- HER2 tested recorded that tumors noteworthy authors Other respectively. The is carcinoma, [170]. 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P, et Formisano A, Penon A, Rizzo S, Kouidhi S, Ricci A, Feola tumorigenesis. [2] to reference with phenomena biochemical few complications: Obesity-related A. Ray M, Ficek R, Farhour K, Iskander [1] References approval: Ethical consent: Informed interest: of Conflict funding: Research Statement support. Author his for Hill, Seton at LECOM President, Vice Freeman, Irv Dr. to thankful is author The Acknowledgments therapeu- anti-HER2 new of development the in HER2 helpful of approaches. is functions understanding tic precise better the A into system. needed physiological is our insight HER2-targeted in more Although results, cardiomyocytes. encouraging in shows HER2 trastuzumab of like effects therapy beneficial suggests Evidence roles. contrasting lar of pathways signaling downstream acti- the also with leptin connected IGF-1. Fascinatingly, are and leptin. HER2 that like molecules signaling adipokines intracellular pro-inflammatory (through several estrogen and vates of androgens) biosynthesis increased of cy- for responsible pro-inflammatory aromatization is and the tissue pathologi- IGF-1, adipose estrogen, few Excess bioavailable development, [181]. abnormal adipokines tumor or as breast tokines such obesity-related considered Regarding commonly [185]. are [184], events around cases cal constitutes cancer which cancer, approxi- breast breast in inflammatory all of overexpressed of risk elevated is 5% an HER2 with associated and are women, obesity and postmenopausal weight in occurs cancer 20% breast mately of majority neoplastic the in that activated frequently certain are utilize which proliferation. systems MAPK, cellular signaling and induce IGF AKT they and where PI3K, that HER2 growth as mechanisms both such potential Interestingly, molecules are cancer. pathways intracellular of protein signaling common development PI3K-like IGF-1 the a aberrant signaling. to is factor and obesity mTOR growth resistance link insulin/IGF-1 the insulin and instance, that adipogenesis noteworthy For metabolism, obesity. is lipid in It peroxisome in roles participates e.g. important actively metabolism, play and lipid components kinase of these biomolecules of of All range [180]. wide (PPAR a gamma with receptor proliferator-activated associated closely is HER2 Perhaps, Conclusion urologic and ovary the cells. of ovarian in tumors HER2 as and such leptin malignancies obesity-related between associated other interaction and/or is of an obesity HER2 documented number hand, COX-2. Studies other a tract, cancers. and the with GI FASN On linked the leptin, HER2. been by have of of influenced pathologies expression tumors also as among are pathways such that lipogenic phenomena suggests Different progression evidence obesity-related/tumor of several body with growing A cancers. of tract effects tumors. synergistic of Therefore, behavior survival. the and significantly proliferation alter cell could with pathways two associated are these they and pathways, both in hso.2017;232:69 Physiol. 2013;35:1 Pathol. J Malays simi- plays possibly HER2 growth, neoplastic and system cardiovascular the in VEGF of functions the Like noting worth is It development. tumor obesity-related of example best the is cancer breast Postmenopausal GI different for factor risk a is Obesity worldwide. burden cancer major a are tract GI the of Malignancies Ray – 0 fbes ainnis[8] 12,[8] oevr repcieo eoaslsau,over- status, menopausal of irrespective Moreover, [183]. [182], [181], malignancies breast of 30% h odce eerhi o eae oete ua raiasuse. animals or human either to related not is research conducted The – uhr tt ofniginvolved. funding no state Authors nomdcneti o applicable. not is consent Informed 77. uhr tt ocnito interest. of conflict no state Authors – 15. γ ,mO,lpn1(hshtdt hshts)adtriglycerides and phosphatase) (phosphatidate lipin-1 mTOR, ), EGRUYTER DE Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 3]SnhB ofe J rmwv art ae rtis h oeo rnfriggot atrapai elhaddsae SeminCellDev disease. and inhealth alpha factor growth role oftransforming the naked proteins: to hair 1990;265:21393 wavy Chem. From Biol RJ. Co昀ffey J B, factors. growth Singh membrane-anchored [36] 2014;28:2 for Biol. model Dev A Cell factor-alpha. Semin growth Transforming bedside. J. to Massagué organization [35] gene from factor, growth Epidermal RC. New Harris F, cancer. Zeng breast [34] in factors related oestrogen other and EGFR, immunoexpression, oncoprotein c-erbB-2 on Study thesis) (Ph.D. A. Expert therapy. Ray cancer [33] in pathway signaling EGFR the Targeting SK. Batra AK, Ganti M, Jain D, MP, Haridas altered P, Ponnusamy through Seshacharyulu promotion [32] tumor skin mouse modulates balance Energy J. DiGiovanni SD, Hursting prognos- S, poor Carbajal a L, is Beltran T, (pIGF1R) Moore receptor factor-1 [31] growth insulin-like Phosphorylated al. et SG, Wu JY, Shih YS, Lu JC, Yang of WC, resistance Huang the PF, Wu in pathway [30] factor-IR growth insulin-like the of Implication HY. Lee WK, Hong F, Ciardiello ES, in Kim EGFR WY, and Kim F, IGF-1R Morgillo involving [29] pathway extra-nuclear an via signals Estrogen W. Yue RX, Song Y, Bao Z, P, Zhang Fan RJ, Santen tamoxifen-resistant [28] in signaling receptor factor-I growth Insulin-like RI. Nicholson JM, Gee D, 1 Barrow factor IR, growth Hutcheson insulin-like JM, and Knowlden receptor [27] factor growth Epidermal al. et CJ, Yeo B, Freydin T, Hyslop JR, Brody M, McDonald ME, receptor Valsecchi factor [26] growth insulin-like between crosstalk Potential al. et T, Takigawa N, Kawarabayashi S, Ogata H, in Tsuda common K, is Hatsuse HER-2 S, and Ueda EGFR [25] IGF-IR, the of Coexpression al. et C, DP, Topham Lovell M, Green H, phosphory- Thomas and S, expression MP, Essapen the Cunningham increasing [24] through maturation oocyte promotes I factor growth Insulin-like L. Chen L, Yang Q, Tang L, Xie [23] receptor factor-1 growth insulin-like the of Activation al. et NG, Lee LB, Vanwagner A, Allak LE, Taniguchi AD, Beckler MJ, Jameson [22] D C, Sell M, Miura A, Ferber D, Coppola [21] In: mechanisms. biological and epidemiology of overview an factors: lifestyle and chemoprevention Cancer NS. Murthy GN, Ray A, Ray [20] 2015;95:727 Rev. 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Veyrat-Durebex biochemistry M, clinical Asrih a [6] cancer: breast and 2012;37:289 MP. Obesity Biosci. Cleary J cancer. A, Ray breast [5] of pathology Investig. obesity-related Clin in Biol leptin Mol Adipokine Horm A. Ray promotion. cancer [4] in role adipokines: and obesity tissue, Adipose M. Foster J, Fouts A, Magnuson A, Booth [3] GRUYTER DE il 2014;28:12 Biol. 2002. Islamia; Millia Jamia Delhi: 2012;16:15 Targets. Ther Opin 2012;5:1236 (Phila). Res Prev Cancer crosstalk. EGFR and IGF-1R 2013;115:61 Neurooncol. J adenocarcinomas. lung from metastases brain in factor tic 2007;13:2795 Res. Cancer Clin gefitinib. with treatment to cells cancer lung cell non-small 2009;74:586 Steroids. cells. cancer breast -resistant and tamoxifen-sensitive 2005;146:4609 Endocrinology. receptor. factor growth epidermal the to role supporting a cancer: breast 2012;118:3484 Cancer. adenocarcinoma. ductal pancreatic in survival poor predict expression receptor 2006;19:788 Pathol. 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J World diabetes. 2006;11:397 Oncologist. 2011;1813:878 Acta. Biophys 2015;70:92 Gerontol. Exp mice. aged in IGF-1 derived 2016;38:1218 Biochem. 2015;21:57 ’ lngnC,Bwr W usigS.Awihypolm eaoi etrain n h bst-acrln.Hr o ilClin Biol Mol Horm link. obesity-cancer the and perturbations metabolic problem: weighty A SD. Hursting LW, Bowers CH, Flanagan – – 42. 74. – – 8. 34. – 21. – – 57. 509. – – 25. 408. – 88. – 31. – – ’ 55. 8. mrsoC ui ,e l ucinlislnlk rwhfco eetri eurdfrthe for required is receptor I factor growth insulin-like functional A al. et R, Rubin C, Ambrosio – 83. – 35. – 6. – 46. – 94. – 70. – – 94. 803. – 207. – 93. – 18. – – 97. 95. – 11. – 84. – 96. Ray – 6. – 48. 13 Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 14 by cancer breast male of subtyping Molecular al. et JJ, Oudejans PC, Bruin de MC, Hogenes H, carcinoma. Buerger breast AH, Verschuur-Maes male R, of Kornegoor subtypes [72] of characterization Immunohistochemical al. et Y, Gong E, Lin Z, Wang MA, ovar- Eltorky in N, expression Sneige Y, EGFR Ge and [71] HER2/NEU receptor, Hormone al. et Y, Kucukzeybek S, Cokmert M, Akyol C, Sadullahoglu S, Yigit borderline L, in overexpression Demir EGFR [70] and Her-2, p53, of significance Prognostic A. Jakobsen K, Bertelsen tumor vascularity B, on Hølund E, Jakobsen expression JS, cyclooxygenase-2 Nielsen of e昀ffect [69] The al. et WD, Lawrence R, Morris JM, Malone I, Khalifeh growth factorre- M, Che epidermal R, HER-2/neu, Ali-Fehmi of [68] andrelationships AM. Overexpression Gown M, HG, Skelly BE, Muntz K, sensi- Greer and paclitaxel Shy BA, survival Go昀ff patient [67] a昀ffects HER-2 of Expression al. et Y, Mizumoto Y, Maida M, Hashimoto M, Nakamura S, papil- Kyo serous N, endometrioid, Mori in [66] PCNA and P53, HER-2/neu, EGFR, of Expression KW. Min J, Walker SD, Haraway in RS, receptor Mannel growth MA, epidermal Khalifa and [65] protein c-erbB-2 of Expression al. et Y, Ishikawa Y, Nanbu M, Mandai M, Koshiyama I, inva- Konishi in D, factors Wang pathobiological [64] associated and oncoprotein c-erbB-2 of Overexpression JK. Sharma S, Sharma S, Kaur BK, receptors Sharma steroid A, and Ray p53, [63] HER2, receptor, factor growth epidermal of Value C. Rose BB, Rasmussen MM, Nielsen Dukes SM, with Bentzen patients AS, in Knoop members [62] family HER of Co-expression H. Modjtahedi AM, Seddon M, Green I, Bagwan S, Essapen SA, and Khelwatty receptor [61] factor-1 growth insulin-like of Relationships al. et J, incoloncan- Matsubara Y, expression Hirashima T, factor Honda receptor NT, 1 growth Okita type Y, Yamada of D, Takahari utility [60] Clinical et T, al. 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Menendez R, Lupu J, (erbB-2) Brunet HER2/neu R, suppresses Colomer (FAS) A, synthase Vazquez-Martin acid [134] fatty of Inhibition al. et R, Colomer S, BP, Ropero Oza I, onco- Mehmi (erbB2) L, HER2/neu Vellon suppresses amentofllavone JA, Menendez by [133] inhibition synthase acid Fatty al. et IS, Song EY, Cha MS, Lee JB, breast Park JY, in Sul oncogene JS, (c-erbB-2) Lee Her-2/neu [132] of status activation the regulate acids fatty Dietary R. Colomer R, Lupu S, Ropero JA, Menendez [131] cancer breast HER2-positive in resistance trastuzumab adipocytokine-mediated of Mechanisms R. JP, Nahta Joshi in KJ, Wang expression SE, beta Griner receptor [130] estrogen suppresses Obesity al. et SD, Hursting RR, Tekmal 2016;28:151 EL, Rossi Investig. AJ, Clin Brenner Biol M, Mol Wiese LW, Horm Bowers system. reproductive [129] male to and atherosclerosis D from P. Vitamin disease: Knoblovits cardiovascular PR, and Costanzo D [128] Vitamin al. et G, Salvio G, Tirabassi S, Karras G, Duval carcinogenesis: C, Annweiler in G, VDR Muscogiuri and [127] D vitamin of role The M. Macías-González FJ, Tinahones G, Martin-Nuñez S, Morcillo July18, B, (Online Merchan 2017 Bandera [126] D.JAutoimmun. byvitamin responses immune and infllammatory of Modulation F. Bonelli B, Jansson F, Steroid Colotta J [125] syndrome. metabolic and diabetes, 2 type obesity, resistance, 2017;165:369 insulin Biol. with Mol D Biochem vitamin Steroid of J Associations tissue. SJ. adipose Wimalawansa in [124] D vitamin of functions my- Physiological rat MA. in Abbas signaling [123] neuregulin-1/ErbB enhanced calcitriol of administration P. Chronic Jiang H, Cai triterpenoid R, synthetic Yang Y, a Zhu analog, Y, D Guo vitamin R, gemini Dang a [122] of administration Oral al. et WJ, Shih Y, Lin AK, Smolarek tumor T, Yoon mammary ErbB2-positive JE, Wahler suppresses JY, analog So D [121] vitamin Gemini al. et H, Maehr S, Paul A, Smolarek A, recurrent breast DeCastro JY, with So apatient HJ, dietin Lee [120] and ketogenic Dsupplementation vitamin pre-surgical of E昀ffects M. sup- Ruggiero S, D Pacini vitamin JJ, with Branca associated [119] outcomes clinical Improved al. et AJ, Montero NJ, Markward Q, Liu N, Shah T, Koru-Sengul of SB, the development Zeichner on [118] supplementation annatto-tocotrienols of E昀ffect M. Provinciali F, Galli F, Orlando A, Barucca 2005;42:15 V, Cancer. Viola J E, Indian Pierpaoli factors. [117] dietary selected of role 2012;4:1622 preventive Nutrients. Cancer biology. A. tissue Ray adipose [116] and micronutrients Lipophilic F. 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Azambuja trastuzumab de and anthracyclines M, for Lambertini NF, factor Pondé risk [111] a as Obesity al. et F, Ghiringhelli S, Ladoire AF, Yu breast D, in Cardinale trastuzumab A, of Lefebvre cardiotoxicity C, developing Guenancia for [110] factors Risk al. et IO, Kara M, Erkisi S, Paydas combina- CU, in Afsar or BB, alone Duman trastuzumab, M, from Gunaldi toxicities [109] of risk The al. et R, Rossello T, Franchina is G, Ferraro (HER2) B, 2 Adamo receptor GR, factor Ricciardi growth V, epidermal Adamo human [108] Circulating al. et K, Sundquist 2012;45:719 K, Rep. Palmer BMB X, cells. Wang epithelial B, breast Zöller human L, in Bennet leptin AA, of Memon expression [107] induces HER2 A. Moon Y, Kang Y, Cha [106] Be [105] 2008;33:111 2013;7:379 Oncol. Mol cells. cancer breast in Hsp90 of up-regulation 2008;149:9 Res. Surg J HER2. of vation 2005;4:1686 Proteomics. 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Pharm Curr therapy. for target and quences ł Ray osiJ Jazmroz-Wi J, towski – 8. ś iwk .Tasciaino rBrcposb etni h adoaclrsse:mcaim,conse- mechanisms, system: cardiovascular the in leptin by receptors ErbB of Transactivation A. niewska – 5. – – 32. – 21. 14. – 41. – 84. – 24. – 21. – – 91. 20. – 6. – 85. – – 77. 60. – 20. – – 18. 24. – 7. – 12. – 65. – 96. – 7. – 81. – – 504. 9. – 23. – 49. EGRUYTER DE – 70. – 11. Automatically generated rough PDF by ProofCheck from River Valley Technologies Ltd 15 lcM lcI pdmooyo acetccne.WrdJGsretrl 2016;22:9694 Gastroenterol. J World cancer. pancreatic 2014;45:362 Endocrine. of reductionist? Epidemiology or I. holistic Ilic cancer: M, and Ilic syndrome [175] Metabolic D. Giugliano a A, lipids: Capuano blood K, abnormal Esposito and [174] obesity diabetes, with patients among Cancer H. Olsson D, Noreen T, Lithman M, tobacco Landin-Olsson with B, associated Attner cancers [173] for Surveillance al. et TF, Pechacek R, 2013;3:187 Kaufmann Biochem. 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D, breast Wang in [165] co-receptor HER2/HER3 of Role JK. Lin receptor. TD, HER2 Way by [164] pathway cyclooxygenase-2 of Regulation R. Kumar J, Mendelsohn G, Steinbach L, Adam M, Mandal R, Vadlamudi [163] of P. The prognosis P, Huang P, and Wu Wu progression X, cancer Bu gastric N, with Li associated [162] are HER-2 and Leptin al. et G, Song Y, Xu K, Wang R, Wang J, Wang Y, hu- Geng in [161] (erbB-2) HER2/neu transactivate Lysophospholipids al. et T, Watanabe K, Mori H, Yamashita H, Yamaguchi the J, attenuates Kitayama protein D, HER-2/neu Shida of [160] Overexpression al. et C, Panis 2008;94:342 AL, Tumori. Cecchini cases. AN, 49 Simão of Colado study AC, clinicopathological Herrera A FC, breast. Campos the VJ, of Victorino 2015;10:e0137204. carcinoma [159] One. Lipid-rich PLoS J. cancer. Sun breast Q, metastatic Zhang in M, proteins P, Wang metabolism-related Shi lipid [158] of hormone- Expression JS. in Koo family receptors HM, factor Kim YY, growth Jung epidermal [157] of Status al. et S, Sharma R, Sood KU, Chaturvedi AK, Bahadur A, Ray D, Jain [156] TNF Increased A. P, Alenad Vanhoutte AK, Mohammed immunohistochemical NM, and Al-Daghri index MS, mass Alokail body [155] between association The al. et Y, Ozisik AR, Sever A, Aytekin F, in Karatas metastases GU, distant Erdem S, of Sahin incidence [154] the increases Obesity al. et S, Caputo D, Galbiati N, Rotmensz V, mass Bagnardi body D, Disalvatore of L, association Tunisia: Mazzarella in [153] cancer Breast al. et S, Chouaib R, implica- Marrakchi clinical N, its Stambouli and S, cancer Labidi breast H, Guissouma in H, (FTO) Bouguerra gene [152] associated obesity and mass fat the of Overexpression Ann review. 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