Different biological effect of estrogen receptor-related receptor α in estrogen receptor-positive and -negative endometrial carcinoma

Estrogen receptor-related receptor α (ERRα) has been identified as a nuclear transfactor closely related to estrogen receptor α (ERα). ERRα interferes with ER-mediated signaling pathways through competition with ERα for the common DNA sites and coregulators. Thus, it may participate in the tumorigenesis of estrogen-related cancers. To elucidate the roles of ERRα in endometrial carcinogenesis and the crosstalk between ERα and ERRα, endometrial carcinoma Ishikawa and HEC-IA cells were treated with different concentrations of 17β-E2 and/or the pure anti-estrogen drug ICI182,780. Using semi-quantitative RT-PCR and Western blot analysis, we found that 17β-E2 down-regulated the expression of ERRα in ER-positive Ishikawa cells, while up-regulating the expression of ERRα in ER-negative HEC-IA cells. Down-regulation in Ishikawa cells was furthermore found to be largely abrogated by ICI182,780. Additionally, we constructed endometrial carcinoma cell lines with overexpression of ERRα by stable transfection, renaming these Ishikawa/ERRα and HEC-IA/ERRα, respectively. To investigate the effect of ERRα overexpression on the biological behavior of the cells, MTT assay and flow cytometry analysis were performed in the constructed cell lines. In ER-positive Ishikawa cells, the overexpression of ERRα inhibited cell growth in the presence of 17β-E2, an inhibitory effect that might be due to a G0-G1 cell cycle arrest. In contrast, overexpression of ERRα stimulated cell proliferation in ER-negative HEC-IA cells independently of 17β-E2. This accelerated action was associated with changes in cell cycle distribution. Our study demonstrates that, in addition to ER, ERRα seems to be an important regulator in endometrial carcinogenesis, playing different roles in estrogen-dependent and -independent endometrial carcinomas. ERRα might modulate the ER-mediated pathways via interference with ERα transcription in endometrial carcinoma cells.