Novel Selective Estrogen Mimics for the Treatment of Tamoxifen-Resistant Breast Cancer

Endocrine-resistantbreastcancerisamajorclinicalobstacle.Theuseof17b-estradiol(E2)hasreemergedasa potentialtreatmentoptionfollowingexhaustiveuseoftamoxifenoraromataseinhibitors,althoughsideeffects have hindered its clinical usage. Protein kinase C alpha (PKCa) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEM) as an alternative to E2 for the treatment of tamoxifen-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKCa-expressing, tamoxifen-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of tamoxifen-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of tamoxifen-resistant T47D:A18/PKCa and T47D:A18-TAM1 tumor models. T47D:A18/PKCa tumor regression was accompanied bytranslocationofestrogenreceptor(ER) atoextranuclearsites,possiblydefiningamechanismthroughwhich theseSEMsinitiatetumorregression.SEMtreatmentdidnotstimulategrowthofE2-dependentT47D:A18/neo tumors. In addition, unlike E2 or tamoxifen, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2. Mol Cancer Ther; 13(11); 2515–26. � 2014 AACR.