Abstract 939: Mechanistic basis of tamoxifen-associated development of endocrine resistance in breast cancer

Abstract

Abstract Many estrogen receptor-positive breast cancers respond well initially to endocrine therapies, but often develop resistance during treatment with SERMs such as tamoxifen. We have reported that the 14-3-3 family member and conserved protein, 14-3-3ζ, is up-regulated by tamoxifen and that high expression correlated with an early time to disease recurrence. However, the mechanism by which tamoxifen up-regulates 14-3-3ζ and may promote the development of endocrine resistance is not known. Our findings reveal that the tamoxifen up-regulation of 14-3-3ζ results from its ability to rapidly down-regulate a microRNA that specifically targets 14-3-3ζ. The levels of 14-3-3ζ and this microRNA were always inversely correlated, with 14-3-3ζ being elevated and the microRNA being at a low down-regulated level in tamoxifen-resistant breast cancer cells. Of note, down-regulation of the microRNA was selectively elicited by tamoxifen but not by other SERMs such as raloxifene or by the estrogen receptor down-regulator ICI182,780 (Fulvestrant). Reducing the cellular level of 14-3-3ζ by either antagomiR blockade of the tamoxifen suppression of the microRNA or by elevation of the intracellular level of the microRNA by over-expression resulted in decreased cell proliferation and colony formation, increased apoptosis, and very importantly, restoration of the growth inhibitory effectiveness of SERMs in endocrine-resistant breast cancer cells. Restoration of responsiveness to endocrine therapy was also accompanied by markedly reduced activation of HER2, EGFR, and MAPK signaling, key components in endocrine resistance. Thus, we identify tamoxifen down-regulation of a microRNA, and consequent elevation of the key survival factor 14-3-3ζ, as a mechanistic basis of tamoxifen-associated development of endocrine resistance. These findings suggest that therapeutic approaches that increase expression of this microRNA should be considered to down-regulate 14-3-3ζ and enhance the effectiveness of endocrine therapies. Furthermore, the observed differential effects of the two SERMs, tamoxifen and raloxifene, in regulation of this microRNA and 14-3-3ζ, may assist in understanding differences in the activities of these SERMs, as seen in the STAR breast cancer prevention trial and in other clinical trials. (Supported by a grant from The Breast Cancer Foundation to BSK and a postdoctoral fellowship from the Department of Defense (W81XWH-09-1-0398) to AB.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 939. doi:10.1158/1538-7445.AM2011-939