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Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth.

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

SUBMITTER: Tiraby C

PROVIDER: S-EPMC3070807 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth.

Tiraby Claire C Hazen Bethany C BC Gantner Marin L ML Kralli Anastasia A

Cancer research 20110221 7

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 ER ...[more]

PMID: 21339306

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Project description:BACKGROUND:Activins belong to the transforming growth factor-? (TGF-?) superfamily of cytokines. Although the role of TGF-? in cancer progression has been highly advocated, the role of activin signaling in cancer is not well known. However, overexpression of activin-A has been observed in several cancers. AIMS:The gene expression profile indicated higher expression of Activin-A in breast tumors. Hence the aim of this study was to evaluate the status and role of Activin signaling pathway in these tumors. METHODS:Microarray analysis was performed to reveal gene expression changes in breast tumors. The results were validated by quantitative PCR and immunohistochemical analysis in two independent sets of normal and tumor samples. Further, correlation of activin expression with survival and distant metastasis was performed to evaluate its possible role in tumor progression. We used recombinant activin-A, inhibitors, overexpression, and knockdown strategies both in vitro and in vivo, to understand the mechanism underlying the protumorigenic role of this signaling pathway. RESULTS:We report that activin-A signaling is hyperactivated in breast cancers as indicated by higher activin-A, phosphoSMAD2, and phosphoSMAD3 levels in advanced breast cancers. Bone morphogenetic proteins and molecules involved in this signaling pathway were downregulated, suggesting its suppression in breast cancers. Activin-A expression correlates inversely with survival and metastasis in advanced breast cancers. Further, activin-A promotes anchorage-independent growth, epithelial-mesenchymal transition, invasion, angiogenesis, and stemness of breast cancer cells. We show that activin-A-induced phenotype is mediated by SMAD signaling pathway. In addition, activin-A expression affects the tumor-forming ability and metastatic colonization of cancer cells in nude mice. CONCLUSIONS:These results suggest that activin-A has a critical role in breast cancer progression and, hence, targeting this pathway can be a valuable strategy in treating breast cancer patients.

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Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth.

Publications

Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth.

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