Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling.

Antiestrogens include agents such as tamoxifen, toremi-fene,raloxifene,andfulvestrant.Currently,tamoxifenisthe only drug approved for use in breast cancerchemoprevention, and it remains the treatment of choiceformostwomenwithhormonereceptorpositive,invasivebreastcarcinoma.Whileantiestrogenshavebeenavailablesincetheearly1970s,westilldonotfullyunderstandtheirmechanisms of action and resistance. Essentially, twoformsofantiestrogenresistanceoccur:de novo resistanceand acquired resistance. Absence of estrogen receptor(ER) expression is the most common de novo resistancemechanism,whereasacompletelossofERexpressionisnot common in acquired resistance. Antiestrogen unre-sponsivenessappearstobethemajoracquiredresistancephenotype, with a switch to an antiestrogen-stimulatedgrowth being a minor phenotype. Since antiestrogenscompete with estrogens for binding to ER, clinicalresponse to antiestrogens may be affected by exogenousestrogenic exposures. Such exposures include estrogenichormone replacement therapies and dietary and environ-mental exposures that directly or indirectly increase atumor’s estrogenic environment. Whether antiestrogenresistance can be conferred by a switch from predomi-nantly ERa to ERb expression remains unanswered, butpredictingresponsetoantiestrogentherapyrequiresonlymeasurement of ERa expression. The role of alteredreceptor coactivator or corepressor expression in anti-estrogen resistance also is unclear, and understandingtheir roles may be confounded by their ubiquitousexpressionandfunctionalredundancy.Wehaveproposeda gene network approach to exploring the mechanisticaspects of antiestrogen resistance. Using transcriptomeand proteome analyses, we have begun to identifycandidategenesthatcompriseonecomponentofalarger,putative gene network. These candidate genes includeNFjB,interferonregulatoryfactor-1,nucleophosmin,andthe X-box binding protein-1. The network also mayinvolve signaling through ras and MAPK, implicatingcrosstalk with growth factors and cytokines. Ultimately,signalingaffectstheexpression/functionoftheprolifera-tionand/orapoptoticmachineries.Oncogene(2003)22,7316–7339.doi:10.1038/sj.onc.1206937Keywords: tamoxifen; Faslodex; ICI 182,780; estrogenreceptor;coregulatorIntroductionAntiestrogensprimarilyactbycompetingwithestrogensfor binding to the estrogen receptor (ER) and are themost widely administered endocrine agents for themanagementofER-expressingbreastcancers.Thefirstantiestrogensweregeneratedinthemid-1950sasfertilityagents and included ethamoxytriphetol (MER-25) andclomiphene. The ability of these compounds to induceresponses in some breast cancer patients soon becameapparent(KistnerandSmith,1960),butthecompoundsinducedsignificanttoxicity(Herbstetal.,1964).Intheearly1970s,thefirststudyinbreastcancerpatientswaspublishedwithanewantiestrogentamoxifen(TAM,ICI46474) (Cole et al., 1971). Over the next 17 years, thetotalexposuretoTAMreached1.5millionpatientyears(Litherland and Jackson, 1988) and other selectiveestrogen receptor modulators (SERMs) are beingdevelopedandstudied.TAMisnowthemostfrequentlyprescribed antiestrogen, and compelling data havedemonstrated asignificantoverall survival benefitwiththeadministrationofthisagentinbreastcancerpatientswith endocrine responsive disease (EBCTCG, 1992,1998).When compared with cytotoxic chemotherapy, anti-estrogens are well tolerated and are associated withmostly minor toxicities (Love, 1989). Common sideeffectsassociatedwithTAMtherapyincludevasomotorsymptoms, gastrointestinal disturbance, atrophic vagi-nitis, and changes in sexual functioning (Day et al.,1999). While the frequency and severity of hot flashesand other toxicities can be particularly unpleasant forsome women, remarkably few discontinue TAM be-