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

Abstract

Estrogen-related receptors (ERR), ERR alpha (ERRα) and ERR gamma (ERRγ), 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 ERRα are associated with poor outcomes whereas high levels of ERRγ are associated with a favorable course. Recent studies suggest that ERRα may indeed promote breast tumor growth. The roles of ERRγ in breast cancer progression and how ERRα and ERRγ may differentially affect cancer growth are unclear. In mammary carcinoma cells that do not express endogenous ERRγ, we found that ectopic expression of ERRγ enhanced oxidative metabolism in vitro and inhibited the growth of tumor xenografts in vivo. In contrast, ectopic expression of the ERRα coactivator PGC-1α enhanced oxidative metabolism but did not affect tumor growth. Notably, ERRγ 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 ERRγ. In contrast, PGC-1α activated only a subset of genes characteristic of the MET program and, unlike ERRγ, did not upregulate E-cadherin. In conclusion, these results show that ERRγ induces E-cadherin, promotes MET, and suppresses breast cancer growth. Our findings suggest that ERRγ agonists may have applications in the treatment of breast cancer.