Function of estrogen-related receptor α in human endometrial cancer

Introduction: The estrogen-related receptor alpha(ERR alpha) is an orphan member of the nuclear receptor superfamily that is closely related to estrogen receptor alpha(ER alpha). ERR alpha binds an estrogen response element ( ERE), directly competes with ER alpha for binding ERE, and represses ERE-dependent transcription in MCF-7 cells, ER-positive breast cancer cells. Objective: We investigated whether ERR alpha modulate some ER-dependent activities in endometrial cancer. Method: We investigated protein and mRNA expression of ERR alpha in endometrial cancer using immunohistochemistry and RT-PCR, respectively. After transient transfection using the ERR alpha expression vector (pCI-ERR alpha) or ERR alpha Si, which suppressed the expression of endogenous ERR alpha, Ishikawa cells were assayed for ERE-dependent luciferase activity. Cells stably overexpressing ERR alpha were generated and compared with estrogen-dependent and - independent cell growth. Result: ERR alpha was detected in human endometrial cancer tissues by immunohistochemistry. An RT-PCR study showed that mRNA of ERR alpha was expressed in four endometrial cancer cell lines (Ishikawa, Hec1a, KLE, and SNGII) and 11 human endometrial tissues. Overexpression of ERR alpha repressed estrogen-induced ERE-dependent transcriptional activity in Ishikawa cells. After transfection with ERR alpha Si1, the expression of endogenous ERR alpha decreased to 0.5-fold, and estrogen-induced ERE luciferase activity increased to 1.5-fold. The cells stably overexpressing ERR alpha grew up more slowly than control cells in the presence of 10 nM estradiol. Conclusion: ERR alpha is expressed in human endometrial cancer tissues and cell lines and suppresses ERE-dependent transcriptional activity in the presence of estrogen. ERR alpha modulates estrogen-induced activity in estrogen-dependent endometrial cancer.