Estrogen Receptor-β Modulation of the ERα-p53 Loop Regulating Gene Expression, Proliferation, and Apoptosis in Breast Cancer

Estrogen receptor alpha (ER alpha) is a crucial transcriptional regulator in breast cancer, but estrogens mediate their effects through two estrogen receptors, ER alpha and ER beta, subtypes that have contrasting regulatory actions on gene expression and the survival and growth of breast cancer cells. Here, we examine the impact of ER beta on the ER alpha-p53 loop in breast cancer. We found that ER beta attenuates ER alpha-induced cell proliferation, increases apoptosis, and reverses transcriptional activation and repression by ER alpha. Further, ER beta physically interacts with p53, reduces ER alpha-p53 binding, and antagonizes ER alpha-p53-mediated transcriptional regulation. ER alpha directs SUV39H1/H2 and histone H3 lys9 trimethylation (H3K9me3) heterochromatin assembly at estrogen-repressed genes to silence p53-activated transcription. The copresence of ER beta in ER alpha-positive cells abrogates the H3K9me3 repressive heterochromatin conformation by downregulating SUV39H1 and SUV39H2, thereby releasing the ER alpha-induced transcriptional block. Furthermore, the presence of ER beta stimulates accumulation of histone H3 lys4 trimethylation (H3K4me3) and RNA polymerase II (RNA Pol II) on ER alpha-repressed genes, inducing H3K4me3-associated epigenetic activation of the transcription of these repressed genes that can promote p53-based tumor suppression. ER beta also reduced corepressor N-CoR and SMRT recruitment by ER alpha that could attenuate the crosstalk between ER alpha and p53. Overall, our data reveal a novel mechanism for ER beta's anti-proliferative and pro-apoptotic effects in breast cancer cells involving p53 and epigenetic changes in histone methylation that underlie gene regulation of these cellular activities.