The role of the corepressor N-CoR1 related to TNF-alpha-mediated apoptosis in Breast cancer cells

Abstract

We have investigated the role of Nuclear Receptor Corepressor1 (NCoR1) in Estrogen Receptor alpha (ERα) (+) breast cancer cells. The NCoR1 plays an important role in the Tumor Necrosis Factor-alpha (TNF-α)-mediated apoptosis. But, mechanism of ERα-NCoR1 complex is little known in breast cancer. Thus, we studied that TNF-α significantly down-regulates NCoR1 protein levels in ERα (+) MCF7 breast cancer cells. In addition, the reduced NCoR1 expression by TNF-α was induced the down-regulation of ERα protein levels in the MCF7 cells. This result suggests that NCoR1 expression may be involved in the TNF-α-mediated apoptosis of ERα (+) breast cancer cells. Interestingly, the phosphorylation of NCoR1 by Casein Kinase2 (CK2) inhibited the ubiquitin-dependent proteasomal degradation of NCoR1 in the TNF-α-treated MCF7 breast cancer cells. In conclusion, the down-regulation of NCoR1 and ERα by TNF-α induced the activation of Tumor suppressor p53 (p53). Thus, our results show that TNF-α treatment induces dissociation of ERα-NCoR1-p53 complex and activates p53-dependent pro-apoptosis target genes through the acetylation of p53. These findings indicate that ERɑ-NCoR1-p53 complex represses the transcription activity of cell death genes, such as cyclin-dependent kinase inhibitor1 (p21), Bcl2-associated-X protein (Bax) and p53 upregulated modulator of apoptosis (Puma).

Keyword : Tumor Necrosis Factor-alpha (TNF-α), Estrogen Receptor alpha (ERα), Nuclear Receptor Corepressor1 (NCoR1), Tumor suppressor p53 (p53), Apoptosis, Breast cancer