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Recruitment of ß-Catenin by Wild-Type or Mutant Androgen Receptors Correlates with Ligand-Stimulated Growth of Prostate Cancer Cells

Cancer Biology Program/Hematology-Oncology Division (D.M., S.-Y.C., Y.X., M.C.V., E.C., 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, Massachusetts 02215; and University of Utrecht (M.C.V.), 3508 GA, Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Steven P. Balk, Hematology-Oncology Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215. 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 steroid receptor coactivator-1 (SRC-1) but did not mediate N-C terminal interactions or recruit ß-catenin, indicating a nonagonist conformation. Nonetheless, CPA did not enhance AR interaction with nuclear receptor corepressor, whereas the AR antagonist RU486 (mifepristone) strongly stimulated AR-nuclear receptor corepressor 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 ß-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 ß-catenin. In contrast, ß-catenin coactivated a bicalutamide-responsive mutant AR (W741C) isolated from a bicalutamide-stimulated LNCaP subline, further implicating ß-catenin recruitment in AR-stimulated growth. Androgen-stimulated prostate-specific antigen gene expression in LNCaP cells could be modulated by ß-catenin, and endogenous c-myc expression was repressed by dihydrotestosterone, but not CPA. These results indicate that interactions between AR and ß-catenin contribute to prostate cell growth in vivo, although specific growth promoting genes positively regulated by AR recruitment of ß-catenin remain to be identified.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR  |  PR  |  AR

Coregulators:   SRC-1  |  NCOR

Ligands:   Dihydrotestosterone  |  RU486  |  Bicalutamide

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