Estrogen-Related Receptor Gamma Promotes Mesenchymal-to-Epithelial Transition and Suppresses Breast Tumor Growth

Estrogen-related receptors (ERR), ERR alpha (ERR alpha) and ERR gamma (ERR gamma), are orphan nuclear receptors implicated in breast cancer that function similarly in the regulation of oxidative metabolism genes. Paradoxically, in clinical studies, high levels of ERR alpha are associated with poor outcomes whereas high levels of ERR gamma are associated with a favorable course. Recent studies suggest that ERR alpha may indeed promote breast tumor growth. The roles of ERR gamma in breast cancer progression and how ERR alpha and ERR gamma may differentially affect cancer growth are unclear. In mammary carcinoma cells that do not express endogenous ERR gamma, we found that ectopic expression of ERR gamma enhanced oxidative metabolism in vitro and inhibited the growth of tumor xenografts in vivo. In contrast, ectopic expression of the ERR alpha coactivator PGC-1 alpha enhanced oxidative metabolism but did not affect tumor growth. Notably, ERR gamma activated expression of a genetic program characteristic of mesenchymal-to-epithelial transition (MET). This program was apparent by changes in cellular morphology, upregulation of epithelial cell markers, downregulation of mesenchymal markers, and decreased cellular invasiveness. We determined that this program was also associated with upregulation of E-cadherin, which is activated directly by ERR gamma. In contrast, PGC-1 alpha activated only a subset of genes characteristic of the MET program and, unlike ERRg, did not upregulate E-cadherin. In conclusion, these results show that ERR gamma induces E-cadherin, promotes MET, and suppresses breast cancer growth. Our findings suggest that ERR gamma agonists may have applications in the treatment of breast cancer. Cancer Res; 71(7); 2518-28. (C)2011 AACR.