Abstract 1733: Therapeutic significance of ERα—PELP1 axis in blocking endocrine therapy resistance

Abstract

Abstract Breast cancer therapies target the estrogen receptor-alpha (ERα) with letrozol an aromatase inhibitor or anti-estrogens such tamoxifen to limit circulating estrogen levels and alter ERα functions. Many women suffering from recurrent or advanced disease develop resistance to current targeted endocrine treatments. Emerging data suggests therapeutic resistance is precipitated through dysfunction of ERα coregulatory proteins and crosstalk between ERα and growth factor signaling. Deregulated expression of proline-, glutamic acid- and leucine-rich protein 1 (PELP1), an ERα coregulator, was observed in a subset of human breast tumors. Recently, PELP1 was identified as an independent prognostic biomarker of shorter survival in ERα positive/luminal-like breast cancer patients. Epigenetic changes of target gene promoters are modulated by PELP1 via an interaction with lysine specific demethylase 1 (KDM1). Additionally, PELP1 promotes crosstalk between ERα and Src kinase leading to enhanced activation of extranuclear signaling pathways. Therapeutic potential of targeting the ERα-PELP1 axis in vivo was examined using a pharmacological approach in well-established preclinical models of endocrine therapy resistant breast cancer. We utilized (1) siRNA liposomes to down regulate PELP1 expression; (2) pargyline and NCL-1, KDM1 inhibitors, to block PELP1-mediated epigenetic modifications and (3) dasatinib, a Src kinase inhibitor, to prevent PELP1-mediated extranuclear actions in both pre- and post-menopausal conditions. In xenograft-based assays, treatment of ERα positive breast cancer cells with liposomes containing PELP1-siRNA, dasatinib or KDM1 inhibitors significantly reduced proliferation and tumor growth. Combinatorial therapies of letrozol or tamoxifen with PELP1 axis blockers substantially impeded xenograft tumor growth by blocking both ERα nuclear and extranuclear signaling and promoting apoptosis in therapy resistant cells. Taken together, our results suggest targeting the ERα-PELP1 axis in combination with current endocrine therapies will enhance therapeutic efficacy and may inhibit or delay development of endocrine therapy resistance. This study is funded by Komen grant KG090447 and NIH grant CA095681. 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 1733. doi:10.1158/1538-7445.AM2011-1733