Novel selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17β-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 (PKCα) 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 PKCα-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/PKCα and T47D:A18-TAM1 tumor models. T47D:A18/PKCα tumor regression was accompanied by translocation of estrogen receptor (ER) α 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.

Original languageEnglish (US)
Pages (from-to)2515-2526
Number of pages12
JournalMolecular cancer therapeutics
Issue number11
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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