Abstract 804: The impact of aromatase inhibitor therapy on ER co-regulator expression and interaction

Abstract

Abstract Estrogen receptor alpha (ERα) is a member of the nuclear receptor family and is currently recognized as the most defining metric in breast cancer diagnosis and treatment. Roughly 70% of all breast cancer patients present with ERα-positive, hormone sensitive disease, and the majority of these women are post-menopausal. Because post-menopausal women require the aromatase enzyme for estrogen synthesis, the first line of treatment for these patients is aromatase inhibitor (AI) therapy. Despite the number of women whose primary disease responds positively, a significant fraction of patients fail to gain any clinical benefit due to intrinsic resistance, or eventually relapse due to acquired resistance to AI therapy. Currently, the biochemical changes underlying both intrinsic and acquired resistance to AI therapy is yet unknown; thus, resistance to AI therapy remains a significant clinical obstacle for a large fraction of breast cancer patients. Here, we investigate the impact of ERα co-regulators on intrinsic and acquired AI resistance in breast cancer. In vitro administration of testosterone to wild-type MCF-7, T47-D, or ZR75-1 cells is capable of offering a significant ERα-dependent proliferative advantage, suggesting an active role for aromatase in these cells. Interestingly, aromatase inhibitor (Anastrazole) treatment of these cells alters the expression of specific ERα co-regulators independent of ligand. Furthermore, interaction between ERα and individual co-regulators is altered after treatment with estradiol or testosterone, and is impacted by Anastrazole treatment acutely. While these findings are preliminary, further investigation is on-going and promises to provide critical insight into the contributions of ERα co-regulators to the short- and long-term response to AI-mediated estrogen deprivation, as well as establish the alterations in ERα-mediated promoter occupancy and gene regulation that contribute to intrinsic and acquired AI resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 804. doi:1538-7445.AM2012-804