Abstract P6-04-30: COUP-TFII suppresses NFκB activation in endocrine-resistant breast cancer cells

Abstract

Abstract COUP-TFII is an orphan nuclear receptor that functions as either a transcriptional activator or repressor. We previously reported that COUP-TFII expression is reduced in endocrine-resistant LCC9 breast cancer cells and that overexpression of COUP-TFII restored the ability of the antiestrogen tamoxifen to inhibit cell proliferation. An increase in NFκB activity and p65/RELA expression 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 can modulate NFκB activity in tamoxifen-resistant breast cancer cells. 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. NFκB activity was elevated in LCC9 TAM-R cells and co-transfection with COUP-TFII reduced NFκB activity. COUP-TFII overexpression led to a statistically significant reduction in the expression of NFκB subunits RELA, RELB, NFKB1, and REL in LCC9 cells. Significantly reduced expression of NFκB target genes IL6, ICAM1, TNFAIP3, and CCL2 was also evident upon COUP-TFII overexpression, reflecting the suppression of the NFκB pathway by COUP-TFII. Inhibition of NFκB activation by COUP-TFII also led to a reduction in cell viability in TAM-R cells in response to tamoxifen treatment. Together these data indicate 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. Supported by NIEHS T32 ES011564 predoctoral fellowship to L.M.L. and Susan G. Komen for the Cure grant KG080365 to C.M.K. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-30.