Abstract 4613: Targeting ER-KDM1 axis to sensitize therapy resistant breast cancer cells to hormonal therapy

Abstract

Abstract Estrogen-induced breast carcinogenesis is characterized by global changes in histone modifications. KDM1 (also known as LSD1) a histone demethylase enzyme, plays a key role in establishing specific histone methylation marks at ERα target gene promoters. Emerging evidence suggests histone methylation imposes ligand dependency; and deregulation of this epigenetic pathway potentially contributes to hormonal independence and adaptive resistance in breast cancer. Our study examined the therapeutic efficacy of pargyline, a KDM1 inhibiting drug, and evaluated the therapeutic benefit to curb growth of therapy resistant breast cancer cells. We used several model cell lines shown to exhibit resistance to hormonal therapy including MCF7-HER2, MCF7-Tam, MCF7-Ca-LTLT, MCF7-PELP1 and parental MCF7 cells as controls. Reporter gene assays showed KDM1 enhanced ERα- mediated transcription in therapy resistant cells. KDM1 functionally interacts with ERα coregulator PELP1 and is co-recruited with PELP1 to ERα target genes. Pargyline treatment substantially inhibited ERα transactivation functions. ChIP analysis revealed distinct activating histone methylation modifications at growth regulatory ERα target genes in aggressively growing and therapy resistant breast cancer cells. Breast cancer models treated with pargyline facilitated reversal of the observed specific modifications and thereby inhibited the growth of breast cancer cells in vitro and in vivo nude mice models. Pargyline also showed significant effect in blocking local estrogen synthesis via alterations in histone methylation modifications at the aromatase promoter. Combinational therapy using three agents that: (a) block ERα's nuclear actions (tamoxifen or letrozole), (b) ERα's extranuclear actions (dasatinib) and (c) ERα's epigenetic modifications (pargyline) showed most promising therapeutic effect compared to single agent therapy on the growth of therapy resistant cells. Our results suggest that histone methylation modifications play a role in therapy resistance and validate the therapeutic potential of pargyline in combinational therapies. Collectively, our results suggests targeting KDM1 axis with pargyline in combination with current endocrine therapies will have better therapeutic effect and may inhibit or delay development of hormonal resistance. This study is funded by Komen grant KG090447. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4613.