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

Estrogen-related receptor alpha(ERRα)is an orphan nuclear factor that is a master regulator of cellular energy metabolism.ERRαis 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 ERRαexpression is associated with an increased rate of recurrence and a poor prognosis.Because of the common functions of ERRαand the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis,we focused on investigating the biochemical relationship between ERRαand S6K1.We found that ERRαnegatively regulates S6K1 expression by directly binding to its promoter.Downregulation of ERRαexpression sensitized ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors.Therefore,our results show that combinatorial inhibition of ERRαand mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer,and warrants further investigation.