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

Abstract

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 beta-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 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 prostate-specific antigen gene expression in LNCaP cells could be modulated by beta-catenin, and endogenous c-myc expression was repressed by dihydrotestosterone, 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.

Evaluation of a variant in the transcription factor 7‐like 2 (TCF7L2) gene and prostate cancer risk in a population‐based study

“…As a mediator of the steroid hormones testosterone and dihydrotestosterone, AR is an essential regulator of prostate growth and function. It has also been demonstrated that β-catenin, as well as TCF7L2 protein, can induce the expression of androgen regulated genes by binding to the AR (26,27). Considering the numerous interactions between Wnt and androgen signaling pathways, together with the growth regulatory role of TCF7L2 protein, we hypothesize that variation in the TCF7L2 gene can influence the development and progression of prostate cancer.…”

PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer

“…b-Catenin can enhance cell proliferation (Mulholland et al, 2003;Masiello et al, 2004), production of PSA and increase AR responsiveness to nonandrogen ligands, including estrogens (Truica et al, 2000;Pawlowski et al, 2002;Song et al, 2003b;Mulholland et al, 2003;. Mice with prostate-specific deletion of the b-catenin regulatory domain (Dexon 3) are reported to develop metaplasia and, in some instances, neoplastic transformation (Bierie et al, 2003;Gounari et al, 2002).…”

“…If PTEN mutational silencing and progressive reduction of GSK3b activity are key factors in promoting transcriptional promiscuity of AR, b-catenin/Tcf, AR/ b-catenin or AR/ARE (androgen response element) interactions could all serve as viable therapeutic options in progressive PrCa. However, as b-catenin appears to mediate increases in cell viability by coactivation of AR, rather than Tcf (Chesire et al, 2002;Masiello et al, 2004;, then small molecule targeting of regions necessary for AR/b-catenin interactions (i.e. b-catenin Arm repeats 5-6; AR LBD helices 3, 12) (Yang et al, 2002;Song et al, 2003a) could be promising.…”

Role of androgen receptor polyQ chain elongation in Kennedy's disease and use of natural osmolytes as potential therapeutic targets

“…Because of the critical role of these coregulators in the AR-mediated gene regulation, any dysregulation of AR:coregulator interactions may perturb normal physiology leading to disease conditions (22). This has been supported by the facts that critical AR interacting coregulators (steroid receptor coactivator-1 [SRC-1] and b-catenin) have been reported as prognosis or diagnostic markers in disease development and progressions (23). In addition, several types of mutations in the AR gene have been linked to endocrine dysfunctions (24).…”