Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth.
Estrogen-related receptor gamma promotes mesenchymal-to-epithelial transition and suppresses breast tumor growth.
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DOI：
10.1158/0008-5472.can-10-1315
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发表时间：
2011-04-01
期刊：
影响因子：
11.2
通讯作者：
Kralli A
中科院分区：
文献类型：
--
作者：
Tiraby C;Hazen BC;Gantner ML;Kralli A
雌激素相关受体α（ERRα）和γ（ERRγ）是与乳腺癌有关的孤儿核受体，在氧化代谢基因的调节中起相似的作用。奇怪的是，在临床研究中，高水平的ERRα与不良结局相关，而高水平的ERRγ与良好的病程相关。最近的研究表明，ERRα确实可能促进乳腺肿瘤的生长。ERRγ在乳腺癌进展中的作用以及ERRα和ERRγ如何不同地影响癌症生长尚不清楚。在不表达内源性ERRγ的乳腺癌细胞中，我们发现ERRγ的异位表达在体外增强了氧化代谢，在体内抑制了肿瘤异种移植物的生长。相反，ERRα辅激活因子PGC-1α的异位表达增强了氧化代谢，但不影响肿瘤生长。值得注意的是，ERRγ激活了间充质-上皮转化（MET）特征性遗传程序的表达。该程序通过细胞形态学的变化、上皮细胞标志物的上调、间充质标志物的下调和细胞侵袭性的降低而明显。我们确定该程序也与E-钙粘蛋白的上调有关，该蛋白直接由ERRγ激活。相比之下，PGC-1α仅激活MET程序特征基因的一个子集，并且与ERRγ不同，不上调E-钙粘蛋白。总之，这些结果表明ERRγ诱导E-cadherin，促进MET并抑制乳腺癌生长。我们的研究结果表明，ERRγ激动剂可能在乳腺癌的治疗中有应用。
Estrogen-Related Receptors alpha (ERRα) and 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 associated also 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.