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• W2783207252 abstract "1580 Mutational inactivation of p53 gene is one of the most frequent events in most cancers. However, p53 mutations are infrequent (20-30%) in breast cancers. In spite of genetically being wild type, why p53 is functionally debilitated in breast cancer has remained unclear. Most (60-80%) breast cancers are estrogen receptor (ER) alpha -positive. Our recent finding that ER alpha binds directly to p53 and inhibits its function has provided a novel mechanism for inactivating genetically wild type p53 in human cancers. Using multiple technical approaches such as immunoprecipitation (IP), chromatin immunoprecipitation (ChIP), GST pull-down assays, gel mobility shift assays, and far western assays, we have demonstrated binding of ER alpha to p53 and have delineated the domains on both the proteins necessary for the interaction. ChIP assays demonstrated that ER interacts with p53 bound to endogenous p21 (CDKN1A) (a prototypic target for transcriptional activation by p53) and survivin and mdr1 (targets for transcriptional repression by p53) resulting in suppression of p53-mediated transcriptional regulation of these genes in human breast cancer cells. Importantly, ionizing radiation disrupted the ER-p53 interaction in vivo both in human cancer cells and human breast tumor xenografts in mice. Intriguingly, 17β-estradiol (E2) has diametrically opposite effects on corepressor recruitment to a p53-target gene promoter versus a prototypic ERE-containing promoter. Sequential ChIP assays and quantitative real-time PCR analysis showed that ER alpha, when bound to p53, recruits transcriptional corepressors such as NCOR resulting in repression of p53-activated genes, as opposed to coactivator recruitment leading to gene activation when ER alpha is bound to ERE on gene promoters. Antiestrogens such as tamoxifen and fulvestrant (ICI 182780) disrupt the ER-p53 interaction and counteract the repressive effect of ER alpha on p53. Thus, we have uncovered a novel mechanism by which estrogen could be providing a strong proliferative advantage to cells by a dual mechanism: enhancing expression of ERE-containing pro-proliferative genes while at the same time inhibiting transcription of p53-dependent anti-proliferative genes. Consistently, ER alpha enhances cell cycle progression and inhibits apoptosis of breast cancer cells. Correlating with these observations, our retrospective clinical study shows that presence of wild type p53 in ER-positive breast tumors is associated with better response to tamoxifen therapy. Thus, our data could provide a new mechanistic basis for resistance to tamoxifen therapy in breast cancer patients. Our findings reveal a novel function of ER alpha and suggest that suppressing p53 function is an important component in the pro-proliferative role of ERα. Further, our observation that antiestrogens disrupted ER-p53 interaction have translational implications." @default.
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• W2783207252 date "2008-05-01" @default.
• W2783207252 modified "2023-10-08" @default.
• W2783207252 title "Inactivation of tumor suppressor p53 by estrogen receptor: Mechanisms of a novel phenomenon with translational implications" @default.
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