Abstract 2214: COUP-TFII suppresses NFκB activation in endocrine-resistant breast cancer cells

Abstract

Abstract COUP-TFII is an orphan nuclear receptor that can function as either a transcriptional activator or repressor. We have previously shown that COUP-TFII expression is reduced in tamoxifen-resistant LCC9 breast cancer cells and that overexpression of COUP-TFII restored the ability of tamoxifen to inhibit cell proliferation. An increase in NFκB activity and p65/RELA level has been reported in endocrine-resistant breast cancer cells. Because NFκB activation results in increased expression of anti-apoptotic and pro-proliferative genes, increased NFκB signaling promotes the survival of cancer cells. The goal of the current study was to further elucidate the mechanism by which COUP-TFII enables cells to maintain endocrine sensitivity and to determine if COUP-TFII modulates NFκB activity in tamoxifen-resistance. To examine whether COUP-TFII can suppress NFκB activity, MCF-7 (tamoxifen-sensitive, TAM-S) and LCC9 (tamoxifen-resistant, TAM-R) breast cancer cells were transfected with a NFκB luciferase reporter and treated with TNFα to activate NFκB. Cotransfection with COUP-TFII reduced NFκB activity in both TAM-S and TAM-R cell lines. Knockdown of COUP-TFII with siRNA led to an increase in p65 expression; conversely, COUP-TFII overexpression led to a suppression of p65 expression. COUP-TFII overexpression also reduced TNFα-induced endogenous NFκB target gene expression. Preliminary data also suggests that suppression of NFκB activation by COUP-TFII leads to a reduction in cell viability in MCF-7 and LCC9 cells in response to tamoxifen and TNFα treatment. This indicates a novel role for COUP-TFII in suppression of NFκB activity which may explain the ability of COUP-TFII to promote tamoxifen-sensitivity. COUP-TFII may be both a useful biomarker to predict tamoxifen-sensitivity as well as a target to restore endocrine sensitivity to resistant cells. 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 2214. doi:1538-7445.AM2012-2214