Abstract LB-27: ERRβ regulates transcriptional activity of ERα as well as ERβ by modulating BCAS2 expression and leads to FST-mediated induction of nuclear fragmentation in ER-positive MCF-7 breast carcinoma cells

Abstract

ERRβ regulates transcriptional activity of ERα as well as ERβ by modulating BCAS2 expression and leads to FST-mediated induction of nuclear fragmentation in ER-positive MCF-7 breast carcinoma cells Dharmendra K Bhargava*, Debomita Sengupta*, Sanjib Choudhary, Rosalima Peter, Dipti Ranjan Mishra, Sandip K Mishra. Corresponding Author *Equal Contribution Institute of Life Sciences (an institute under Department of Biotechnology, Govt. of INDIA), Nalco Square, Bhubaneswar, Odisha, INDIA Abstract: Estrogen related receptors (ERRs) are a group of nuclear receptors which are structurally and functionally related to Estrogen receptors, but do not bind to Estrogen. Diethylstilbestrol, which has been shown to act as a ligand of ERRs, can inhibit growth of ER-positive as well as Tamoxifen-resistant ER negative Breast Cancer cell lines and thus justifies the need of study of ERR target genes for therapeutic purpose. ERRβ has been shown to behave differently from ERRα and ERRγ in terms of regulating tumorigenesis. ERRβ expression level has been shown to be inversely co-related with S-phase fraction suggesting their role in inhibition of cellular proliferation. We have undertaken the current study to identify the common targets of Estrogen Receptors and ERR beta. Study of cross talk between ERRβ and ERα may unfold the mechanism of deregulation of ER alpha signaling leading to failure of cell cycle checkpoint induction or apoptosis in breast cancer cells. By chromatin immunoprecipitation cloning, we identified Breast Cancer Amplified Sequence 2 (BCAS2) and Follistatin (FST) to be two important target genes of ERRβ. Whereas BCAS2 is a coactivator of ER alpha as well as negative coregulator of p53, FST has been shown to enhance the ability of R30C breast carcinoma cells to undergo apoptosis and inhibit multi-organ metastasis of small cell lung carcinoma in natural-killer cell deprived SCID mice. Although, FST and BCAS2 are found to be targets of ERRβ, surprisingly FST expression is upregulated by 10 nM estrogen treatment, while BCAS2 is downregulated. This is indicative of involvement of ER alpha in the regulation of ERRβ target genes. The analysis of our western data revealed that FST activation is mediated by ERRβ. Further, our confocal analysis indicates that ERRβ is able to induce nuclear fragmentation in presence of estrogen in ER positive MCF-7 breast carcinoma cells. Additionally, our first time report on regulation of BCAS2 by ERRβ also provides direct evidence of modulation of ER α transcriptional activity by ERR beta. Our extensive study is clearly inclined towards the need of considering the prognostic importance of ERRβ in ER-positive breast tumors. 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 LB-27. doi:1538-7445.AM2012-LB-27