Reduced COUP-TFII expression contributes to endocrine resistance in breast cancer cells. Endocrine-resistant breast cancer cells have higher NFkappa B (NFκB) activity and target gene expression. The goal of this study was to determine if COUP-TFII modulates NFκB activity. Endocrine-resistant LCC9 cells with low endogenous COUP-TFII displayed ∼5-fold higher basal NFκB activity than parental endocrine-sensitive MCF-7 breast cancer cells. Transient transfection of LCC9 cells with COUP-TFII inhibited NFκB activation and reduced NFκB target gene expression. COUP-TFII and NFκB were inversely correlated in breast cancer patient samples. Endogenous COUP-TFII coimmunoprecipitated with NFκB subunits RelB and NFκB1 in MCF-7 cells. COUP-TFII inhibited NFκB-DNA binding in vitro and impaired coactivator induced NFκB transactivation. LCC9 cells were growth-inhibited by an NFκB inhibitor and 4-hydroxytamoxifen compared to MCF-7 cells. Together these data indicate a novel role for COUP-TFII in suppression of NFκB activity and explain, in part, why decreased COUP-TFII expression results in an endocrine-resistant phenotype.
Keywords: 4-OHT; 4-hydroxytamoxifen; A20/TNFAIP3; Antiestrogens; COUP-TFII; Drug resistance; ERα; ICAM1; IL6; NFκB/NFkappa B; Nuclear receptors; RE; SERD; SERM; TAM; TNFα; TNFα-induced protein 3; Tamoxifen; Transcription factors; chicken ovalbumin upstream promoter transcription factor II; estrogen receptor; intercellular adhesion molecule 1; interleukin 6 (IL6); nuclear factor κB; qPCR; quantitative real-time PCR; response element; selective estrogen receptor downregulator; selective estrogen receptor modulator; tamoxifen; tumor necrosis factor.
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