SIRT1 represses estrogen-signaling, ligand-independent ER alpha-mediated transcription, and cell proliferation in estrogen-responsive breast cells

In prostate and breast cancer, the androgen receptor and estrogen receptor (ER) mediate induction of androgen- and estrogen-responsive genes respectively and stimulate cell proliferation in response to the binding of their cognate steroid hormones. Sirtuin 1 (SIRT1) is a NAD+-dependent class III histone deacetylase that has been linked to gene silencing, control of the cell cycle, apoptosis, and energy homeostasis. In prostate cancer, SIRT1 is required for androgen antagonist-mediated transcriptional repression and growth suppression of prostate cancer cells. Whether SIRT1 plays a similar role in the actions of estrogen or antagonists had not been determined. We report here that SIRT1 represses the transcriptional and proliferative response of breast cancer cells to estrogens, and this repression is ER alpha dependent. Inhibition of SIRT1 activity results in the phosphorylation of ERa in an AKT-dependent manner, and this activation requires phosphoinositide 3-kinase activity. Phosphorylated ER alpha subsequently accumulates in the nucleus, where ER alpha binds DNA ER-responsive elements and activates transcription of estrogen-responsive genes. This ER-dependent transcriptional activation augments estrogen-induced signaling, but also activates ER signaling in the absence of estrogen, thus defining a novel and unexpected mechanism of ligand-independent ER alpha-mediated activation and target gene transcription. Like ligand-dependent activation of ER alpha, SIRT1 inhibition-mediated ER alpha activation in the absence of estrogen also results in breast cancer cell proliferation. Together, these data demonstrate that SIRT1 regulates the most important cell signaling pathway for the growth of breast cancer cells, both in the presence and the absence of estrogen.