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ERR Suppresses Cell Proliferation and Tumor Growth of Androgen-Sensitive and Androgen-Insensitive Prostate Cancer Cells and Its Implication as a Therapeutic Target for Prostate Cancer

Departments of ¹ Anatomy and ² Surgery, The Chinese University of Hong Kong, Shatin, and ³ Department of Anatomy, The University of Hong Kong, Hong Kong, China; and ⁴ Department of Surgical Research, Beckman Research Institute of the City of Hope, Duarte, California

Requests for reprints: Franky L. Chan, Department of Anatomy, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China. Phone: 852-2609-6841; Fax: 852-2603-5031; E-mail: franky-chan{at}cuhk.edu.hk.

Estrogen receptor-related receptors (ERR) are orphan nuclear receptors, which are constitutively activated without estrogen binding. Recent evidence indicates that the ligand-independent ERRs may be involved in similar ER-mediated regulatory pathways and modulate estrogen responsiveness in certain target cells. We recently showed that an ERR subtype, ERR, is coexpressed with ERß in normal human prostatic epithelial cells and exhibits reduced expression in many prostate cancer cell lines and clinical neoplastic prostate tissues. Based on this, we hypothesize that ERR may have growth regulatory roles in prostate and prostate cancer. We showed in this study that ERR was expressed in epithelial cell nuclei in fetal and pubertal human prostates, whereas its nuclear expression became reduced in advanced prostate cancer lesions. Stable ERR expression by retroviral transduction suppressed significantly both in vitro cell growth and in vivo tumorigenicity of two prostate cancer cell lines, LNCaP and DU145, as evidenced by a cell-cycle arrest at G₁-S transition and also induction of two cyclin-dependent kinase inhibitors p21^WAF1/CIP1 and p27^KIP1. We further showed by reporter assay that induction of p21 and p27 by ERR was mediated through direct transactivation of their gene promoters. Moreover, we also showed that a selective ERR-agonist, DY131, could potentiate the ERR-induced growth inhibition in LNCaP-ERR and DU145-ERR cells in a dose-dependent manner compared with respective parental cells. Taken together, our results show that ERR may perform an antiproliferative or tumor-suppressing function in prostate cancer cells. More importantly, our results suggest that ERR could be a novel therapeutic target for prostate cancer treatment. [Cancer Res 2007;67(10):4904–14]

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