Abstract 112: FTY720-P is a potent inhibitor of class I histone deacetylases that enhances histone acetylation, reactivates ERα expression, and increases hormonal therapeutic sensitivity of breast cancer

Abstract

Abstract Hormonal therapies, including ovarian ablation, ER antagonists, and aromatase inhibitors, are the standards of care for treatment of ERα positive breast cancer. However, development of resistance to hormone therapies in advanced breast cancer is a major obstacle. Moreover, estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional estrogen targeted therapies. Strategies that lead to re-expression of ERα could sensitize breast cancers to selective ER modulators. FTY720/Fingolimod, a sphingosine analog, is an FDA-approved pro-drug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We have now found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P in turn is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and gene expression independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. In ERα negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, oral administration of clinically relevant doses of FTY720 to mice bearing ERα negative syngeneic breast tumors also re-expressed ERα and increased therapeutic sensitivity to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that FTY720 is a promising strategy for effective treatment of conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer. Supported by NIH grant RO1CA061774 and the Department of Defense BCRP program award W81XWH-14-1-0086 (S. Spiegel). Citation Format: Nitai C. Hait, Dorit Avni, Akimitsu Yamada, Sheldon Milstien, Kazuaki Takabe, Sarah Spiegel. FTY720-P is a potent inhibitor of class I histone deacetylases that enhances histone acetylation, reactivates ERα expression, and increases hormonal therapeutic sensitivity of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 112. doi:10.1158/1538-7445.AM2015-112