Abstract 1464: Significance and therapeutic potential of PELP1 axis in ER-negative breast cancer

Abstract

Abstract The molecular basis of breast cancer progression to metastasis remains poorly understood. Even though ER and PR explain the biology of ER-positive tumors; it remains unknown as to what drives ER-negative metastatic tumors. PELP1 is an ER coregulator that functions as a proto-oncogene, its expression is deregulated in metastatic breast tumors and its expression is retained in ER-negative tumors. In this study, we examined the mechanism and significance of PELP1 mediated signaling in ER-negative breast cancer progression. We have established ER-negative model cells (MDA-MB231 and 4T1 cells) that stably express PELP1-shRNA. These model cells showed decreased PELP1 expression (75% of endogenous levels) and exhibited decreased propensity to proliferate in in vitro growth assays. Boyden chamber and wound healing assays showed PELP1 down regulation substantially affect migration of ER-negative cells and showed alterations in the expression of the EMT markers. Focused microarray studies identified PELP1 modulate expression of eight genes involved in the EMT (including MMPs, E-cadherin, MTA1). Overexpression of PELP1 in nonmetastatic cells increases their propensity for metastasis in vivo xenograft assays, while, PELP1 knockdown in metastatic model cells decreased in vivo metastatic potential of ER negative breast cancer cells. Whole genome microRNA array analysis revealed that miR 200a and miR141 were upregulated in MDA-MB231 and 4T1 cells expressing PELP1-shRNA compared to control shRNA expressing cells. Over expression of PELP1 in low metastatic model cells decreased expression of miR 200a and miR141. Mechanistic studies showed PELP1 down regulate expression of metastasis suppressive microRNAs (miR 200a and miR141) by promoting chromatin modifications. Ectopic expression of miR 200a and miR141 mimetics decreased PELP1 oncogenic function in ER-negative cells. These results suggest that PELP1 play a role in ER-negative breast cancer metastasis by promoting cell motility / EMT by modulating microRNA expression and blockage of PELP1 axis has potential to reduce metastasis potential of ER-negative breast cancer cells. Understanding how NR coregulator PELP1 plays a role in metastasis will be useful in maximizing treatment opportunities for metastatic breast cancer. 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 1464. doi:10.1158/1538-7445.AM2011-1464