Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)- and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonist-bound AR has a preference for N-CoR. The AR mutation T877A (Thr877→Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of N-CoR. The agonistic activities of CPA- and hydroxyflutamide-occupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.
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Research Article|
May 01 2004
Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)
Cor A. BERREVOETS;
Cor A. BERREVOETS
1
*Department of Reproduction and Development, Erasmus MC, University Medical Center Rotterdam, 3000 DR Rotterdam, Netherlands
1To whom correspondence should be addressed (e-mail c.berrevoets@erasmusmc.nl).
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Arzu UMAR;
Arzu UMAR
*Department of Reproduction and Development, Erasmus MC, University Medical Center Rotterdam, 3000 DR Rotterdam, Netherlands
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Jan TRAPMAN;
Jan TRAPMAN
†Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center Rotterdam, 3000 DR Rotterdam, Netherlands
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Albert O. BRINKMANN
Albert O. BRINKMANN
*Department of Reproduction and Development, Erasmus MC, University Medical Center Rotterdam, 3000 DR Rotterdam, Netherlands
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Publisher: Portland Press Ltd
Received:
September 23 2003
Revision Received:
December 22 2003
Accepted:
January 27 2004
Accepted Manuscript online:
January 27 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 379 (3): 731–738.
Article history
Received:
September 23 2003
Revision Received:
December 22 2003
Accepted:
January 27 2004
Accepted Manuscript online:
January 27 2004
Citation
Cor A. BERREVOETS, Arzu UMAR, Jan TRAPMAN, Albert O. BRINKMANN; Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR). Biochem J 1 May 2004; 379 (3): 731–738. doi: https://doi.org/10.1042/bj20031456
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