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Expression and Functional Study of Estrogen Receptor-Related Receptors in Human Prostatic Cells and Tissues

Departments of Anatomy (C.P.C., S.Y., F.L.C.), Anatomical and Cellular Pathology (F.M.M.L.), Biochemistry (K.B.W.), and Surgery (L.W.C.), The Chinese University of Hong Kong, Hong Kong, China; Department of Anatomy (X.W.), University of Hong Kong, Hong Kong, China; and Beckman Research Institute of the City of Hope (M.S., S.C.), Duarte, California 91010

Address all correspondence and requests for reprints to: Franky L. Chan, Department of Anatomy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China. E-mail: franky-chan{at}cuhk.edu.hk.

Estrogen receptor-related receptors (ERRs; , ß, ) are orphan nuclear receptors and constitutively active without binding to estrogen. Like estrogen receptors (ERs), ERRs bind to estrogen receptor elements and estrogen receptor element-related repeats. Growing evidence suggests that ERRs can cross-talk with ERs in different cell types via competition for DNA sites and coactivators. We hypothesize that ERRs might play regulatory roles in normal and neoplastic prostatic cells by sharing similar ER-mediated pathways or acting independently. In this study, we investigated mRNA and protein expression patterns of three ERR members in normal human prostate epithelial cells, established cell lines, cancer xenografts, and prostatic tissues. Additionally, effects of transient transfection of ERRs on prostatic cell proliferation and ER expression were also examined. RT-PCR showed that ERR and ERR transcripts were detected in most cell lines and xenografts, whereas ERRß was detected in normal epithelial cells and few immortalized cell lines but not in most cancer lines. Similar results were demonstrated in clinical prostatic specimens. Western blottings and immunohistochemistry confirmed similar expression patterns that ERR proteins were detected as nuclear proteins in epithelial cells, whereas their expressions became reduced or undetected in neoplastic prostatic cells. Transient transfection confirmed that ERRs were expressed in prostatic cells as nuclear proteins and transcriptionally active in the absence of estradiol. Transfection results showed that overexpression of ERRs inhibited cell proliferation and repressed ER transcription in PC-3 cells. Our study shows that ERRs, which are coexpressed with ERs in prostatic cells, could regulate cell growth and modulate ER-mediated pathways via interference on ER transcription in prostatic cells.

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