Journal
MOLECULAR CANCER THERAPEUTICS
Volume 13, Issue 11, Pages 2515-2526Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-14-0319
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- NCI/NIH [RO1 CA122914, R01 102590]
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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. (C) 2014 AACR.
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