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ERRgamma 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.

Abstract：

: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, ERRgamma, is coexpressed with ERbeta 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 ERRgamma may have growth regulatory roles in prostate and prostate cancer. We showed in this study that ERRgamma was expressed in epithelial cell nuclei in fetal and pubertal human prostates, whereas its nuclear expression became reduced in advanced prostate cancer lesions. Stable ERRgamma 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 G(1)-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 ERRgamma was mediated through direct transactivation of their gene promoters. Moreover, we also showed that a selective ERRgamma-agonist, DY131, could potentiate the ERRgamma-induced growth inhibition in LNCaP-ERRgamma and DU145-ERRgamma cells in a dose-dependent manner compared with respective parental cells. Taken together, our results show that ERRgamma may perform an antiproliferative or tumor-suppressing function in prostate cancer cells. More importantly, our results suggest that ERRgamma could be a novel therapeutic target for prostate cancer treatment.

journal_name

Cancer Res

journal_title

Cancer research

authors

Yu S,Wang X,Ng CF,Chen S,Chan FL

doi

10.1158/0008-5472.CAN-06-3855

subject

Has Abstract

pub_date

2007-05-15 00:00:00

pages

4904-14

issue

eissn

0008-5472

issn

1538-7445

pii

67/10/4904

journal_volume

pub_type

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ERRgamma 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.