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

作者：Molloy Mary Ellen; White Bethany E Perez; Gherezghiher Teshome; Michalsen Bradley T; Xiong Rui; Patel Hitisha; Zhao Huiping; Maximov Philipp Y; Jordan V Craig; Thatcher Gregory R J; Tonetti Debra A^*

来源：Molecular Cancer Therapeutics, 2014, 13(11): 2515-2526.

DOI：10.1158/1535-7163.MCT-14-0319

Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17 beta-estradiol (E2) has reemerged as a potential treatment option following exhaustive use of tamoxifen or aromatase inhibitors, although side effects have hindered its clinical usage. Protein kinase C alpha (PKC alpha) 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 PKC alpha-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/PKC alpha and T47D:A18-TAM1 tumor models. T47D:A18/PKC alpha tumor regression was accompanied by translocation of estrogen receptor (ER) alpha to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D: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.

• 出版日期2014-11