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Function of Estrogen-Related Receptor in Human Endometrial Cancer

Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kyoto 602-8566, Japan

Address all correspondence and requests for reprints to: Dr. Yoshiyuki Kinoshita, Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: ykino{at}koto.kpu-m.ac.jp.

Introduction: The estrogen-related receptor (ERR) is an orphan member of the nuclear receptor superfamily that is closely related to estrogen receptor (ER). ERR binds an estrogen response element (ERE), directly competes with ER for binding ERE, and represses ERE-dependent transcription in MCF-7 cells, ER-positive breast cancer cells.

Objective: We investigated whether ERR modulate some ER-dependent activities in endometrial cancer.

Method: We investigated protein and mRNA expression of ERR in endometrial cancer using immunohistochemistry and RT-PCR, respectively. After transient transfection using the ERR expression vector (pCI-ERR) or ERRSi, which suppressed the expression of endogenous ERR, Ishikawa cells were assayed for ERE-dependent luciferase activity. Cells stably overexpressing ERR were generated and compared with estrogen-dependent and -independent cell growth.

Result: ERR was detected in human endometrial cancer tissues by immunohistochemistry. An RT-PCR study showed that mRNA of ERR was expressed in four endometrial cancer cell lines (Ishikawa, Hec1a, KLE, and SNGII) and 11 human endometrial tissues. Overexpression of ERR repressed estrogen-induced ERE-dependent transcriptional activity in Ishikawa cells. After transfection with ERRSi1, the expression of endogenous ERR decreased to 0.5-fold, and estrogen-induced ERE luciferase activity increased to 1.5-fold. The cells stably overexpressing ERR grew up more slowly than control cells in the presence of 10 nM estradiol.

Conclusion: ERR is expressed in human endometrial cancer tissues and cell lines and suppresses ERE-dependent transcriptional activity in the presence of estrogen. ERR modulates estrogen-induced activity in estrogen-dependent endometrial cancer.