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

Estrogen-related receptors (ERR), ERR alpha (ERRa) and ERR gamma (ERRg), 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 ERRa are associated with poor outcomes whereas high levels of ERRg are associated with a favorable course. Recent studies suggest that ERRa may indeed promote breast tumor growth. The roles of ERRg in breast cancer progression and how ERRa and ERRg may differentially affect cancer growth are unclear. In mammary carcinoma cells that do not express endogenous ERRg , we found that ectopic expression of ERRg enhanced oxidative metabolism in vitro and inhibited the growth of tumor xenografts in vivo. In contrast, ectopic expression of the ERRa coactivator PGC-1a enhanced oxidative metabolism but did not affect tumor growth. Notably, ERRg activated expression of a genetic program characteristic of mesenchymal-toepithelial 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 programwas also associated with upregulation of E-cadherin, which is activated directly by ERRg . In contrast, PGC-1a 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 ERRg induces E-cadherin, promotes MET, and suppresses breast cancer growth. Our findings suggest that ERRg agonists may have applications in the treatment of breast cancer. Cancer Res; 71(7); 2518–28. 2011 AACR.