Abstract 5753: Potential therapeutic use of ER beta modulators in treating endocrine therapy resistant breast cancers

Abstract

Abstract Although systemic hormone therapies that either block local estrogen production by aromatase inhibitors (AI) such as letrozole or block actions of estrogen/ER actions by anti-estrogens (AEs) like tamoxifen are well tolerated, unfortunately, essentially all breast cancers in women with advanced breast cancer develop resistance to these agents, and the benefit of adjuvant therapy is also limited by the development of resistance. In addition, side effects associated with the systemic inhibition of aromatase with current compounds limits their long-term utility of them as chemopreventative agents. Using in vitro and preclinical postmenopausal breast cancer models, we have investigated whether treatment of endocrine therapy resistant (AI or AE) breast cancer cells with selective plant-derived ER beta agonists (Liquiritigenin; LIQ or Nyasol; NYA) alone or in combination with AE or AI affects the growth of resistant breast cancer cells, thereby restores sensitivity to AE or AI. To test whether combination therapy restores sensitivity to letrozole or tamoxifen, we have treated resistant breast cancer cells with either letrozole or tamoxifen alone or with a combination of AE or AI and LIQ/NYA, active ingredient of MF101 used for treatment hot flashes in postmenopausal women. In addition, an effect of these compounds on cell growth was also tested using different breast cancer cells with and without ERα including triple negative breast cancer cells. Efficacy of these drugs was also tested in these model cells with or without ERβ expression. Compared to single agents, combination treatment not only restored sensitivity to letrozole but also resulted in decreased cell proliferation and increased apoptosis as well as increased ERβ and decreased ERα levels in resistant cells. Combination of LIQ or NYA not only diminished cell growth various breast cancer cells (that express endogenous aromatase) but also affected the expression of aromatase. Detailed investigations indicated that LIQ/NYA affects the induction of aromatase by specifically inhibiting breast cancer specific aromatase promoter 1.3 as well as its activity through inflammatory cytokine-mediated actions. ERβ-mediated inhibition of tumor cell growth appears to be regulated by different molecular mechanisms. Some of these molecular pathways are different than that are known to be responsible for resistance to hormonal therapeutic agents. These studies suggest the therapeutic benefit of LIQ or NYA ERβ agonist to resensitize breast cancer cells that are resistant to AEs or AI and their ability to selectively inhibit tumor induction of aromatase. Our study suggests a novel role of natural ER beta agonists as valuable therapeutic modulators to treat endocrine sensitive as well as resistant tumors. 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 5753. doi:1538-7445.AM2012-5753