Abstract
Abstract Endocrine therapy is a key component of adjuvant therapy for estrogen receptor (ER)-positive breast cancer. However, initial or acquired resistance frequently occurs and tumor recurs as advanced metastatic disease. Accumulating evidence suggests that ER-coregulators play an essential role in cancer progression. Metastatic tumors exhibit increased expression of coregulators and their deregulation occurs in both ER+ve and ER-ve tumors. Proline glutamic acid rich protein (PELP1) is an ER coregulator, its expression is upregulated during breast cancer progression to metastasis and PELP1 is an independent prognostic predictor of shorter breast cancer specific survival. The objective of this study is to examine the mechanism and significance of PELP1 regulation of microRNAs and its effect on breast cancer metastasis. We have used both ER+ve (ZR75, MCF7) and ER-ve (MDAMB231) models that either stably overexpress PELP1 or PELP1shRNA. Boyden chamber, wound healing, and invasion assays demonstrated that PELP1 down regulation significantly affect migration of both ER+ve and ER-ve cells. Epithelial to Mesenchymal Transition (EMT) real time qPCR Array (Super array) studies identified PELP1 modulate expression of eight genes involved in the EMT (including Snail, Twist, ZEB1, ZEB2, Vimentin and MMPs). In xenograft assays, overexpression of PELP1 in non-metastatic ZR75, MCF7 cells increased their propensity for metastasis in vivo, while PELP1 knockdown in metastatic MDAMB231 model cells decreased in vivo metastasis. Mechanistic studies using whole genome microRNA array analysis using PELP1 model cells revealed that miR200a and miR141 were significantly upregulated in cells expressing PELP1-shRNA compared to control shRNA expressing cells. Accordingly, over expression of PELP1 in low metastatic model cells decreased expression of miR200a and miR141. Chromatin immunoprecipitation (ChIP) analysis revealed recruitment of PELP1 to the proximal promoter region of miR-200a and miR141. Mechanistic studies showed PELP1 down regulate expression of metastasis suppressive microRNAs (miR200a and miR141) by promoting repressive chromatin modifications via its association with HDAC2. Accordingly, HDAC inhibitors reversed PELP1 driven repressive effects. Further, ectopic expression of miR200a and miR141 mimetics decreased PELP1 mediated metastatic functions. Collectively, these findings demonstrate for the first time a previously unknown role for PELP1 in the epigenetic control of miR-200a and miR141. These results reveal that PELP1 play a role in breast cancer metastasis by promoting cell motility / EMT by modulating miRNA expression. Understanding how proto-oncogene PELP1 plays a role in metastasis will be useful in maximizing treatment opportunities for metastatic breast cancer. This study is funded by T32CA148724 NIH Postdoctoral Fellowship Grant. 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 2301. doi:1538-7445.AM2012-2301
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