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This version published online on July 15, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0436
Molecular Endocrinology Vol. 0, No. 2004 200304361-
doi:10.1210/me.2003-0436
Copyright © 2004 by the Endocrine Society.
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*Prostate Cancer

Submitted on November 11, 2003
Accepted on July 7, 2004

RECRUITMENT OF {beta}-CATENIN BY WILD TYPE OR MUTANT ANDROGEN RECEPTORS CORRELATES WITH LIGAND STIMULATED GROWTH OF PROSTATE CANCER CELLS

David Masiello, Shao-Yong Chen, Youyuan Xu, Manon C. Verhoeven, Eunis Choi, Anthony N. Hollenberg, and Steven P. Balk*

Cancer Biology Program/Hematology-Oncology Division (D.M., S.C, Y.X., E.C., M.C.V., S.P.B.) and the Thyroid Unit/Endocrinology Division (A.N.H.), Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215; University of Utrecht, Utrecht, The Netherlands (M.C.V.)

* To whom correspondence should be addressed. E-mail: sbalk{at}bidmc.harvard.edu.

Prostate cancers respond to treatments that suppress androgen receptor (AR) function, with bicalutamide, flutamide, and cyproterone acetate (CPA) being AR antagonists in clinical use. As CPA has substantial agonist activity, it was examined to identify AR coactivator/corepressor interactions that may mediate androgen stimulated prostate cancer growth. The CPA liganded AR was coactivated by SRC-1, but did not mediate N-C terminal interactions or recruit {beta}-catenin, indicating a non-agonist conformation. Nonetheless, CPA did not enhance AR interaction with NCoR, while the AR antagonist RU486 (mifepristone) strongly stimulated AR-NCoR binding. The role of coactivators was further assessed with a T877A AR mutation, found in LNCaP prostate cancer cells, which converts hydroxyflutamide (HF, the active flutamide metabolite) into an agonist that stimulates LNCaP cell growth. The HF and CPA liganded T877A ARs were coactivated by SRC-1, but only the HF liganded T877A AR was coactivated by {beta}-catenin. L-39, a novel AR antagonist that transcriptionally activates the T877A AR, but still inhibits LNCaP growth, similarly mediated recruitment of SRC-1 and not {beta}-catenin. In contrast, {beta}-catenin coactivated a bicalutamide responsive mutant AR (W741C) isolated from a bicalutamide stimulated LNCaP subline, further implicating {beta}-catenin recruitment in AR stimulated growth. Androgen stimulated PSA gene expression in LNCaP cells could be modulated by {beta}-catenin, and endogenous c-myc expression was repressed by DHT, but not CPA. These results indicate that interactions between AR and {beta}-catenin contribute to prostate cell growth in vivo, although specific growth promoting genes positively regulated by AR recruitment of {beta}-catenin remain to be identified.
Key words: androgen receptor • {beta}-catenin • prostate cancer • steroid hormone receptor • cyproterone acetate • testosterone • RU486 • coactivator • corepressor

NURSA Molecule Pages Link:

Nuclear Receptors:   GR  |  PR  |  AR
Coregulators:   SRC-1  |  NCOR
Ligands:   Dihydrotestosterone  |  RU486  |  Bicalutamide



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