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

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