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

Abstract

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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 11 Pg. 2515-26 (Nov 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 25205655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Estrogens
• Receptors, Estrogen
• Thiophenes
• benzothiophene
• Tamoxifen

Topics

• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Progression
• Estrogens (chemistry)
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Nude
• Random Allocation
• Receptors, Estrogen (metabolism)
• Tamoxifen (pharmacology)
• Thiophenes (pharmacology)
• Transfection
• Xenograft Model Antitumor Assays