ERRα regulates the growth of triple-negative breast cancer cells via S6K1-dependent mechanism

Estrogen-related receptor alpha (ERR alpha) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERR alpha is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERR alpha expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERR alpha and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERR alpha and S6K1. We found that ERR alpha negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRa expression sensitized ER alpha-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERR alpha and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation.