Androgen regulation of gene expression.

Department of Urology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Advances in Cancer Research (Impact Factor: 6.35). 01/2010; 107:137-62. DOI: 10.1016/S0065-230X(10)07005-3
Source: PubMed

ABSTRACT The biological action of androgenic male sex steroid hormones in prostate tissue is mediated by the androgen receptor, a nuclear transcription factor. The transcriptional program of androgenic signaling in the prostate consists of thousands of gene targets whose products play a role in almost all cellular functions, including cellular proliferation, survival, lipid metabolism, and differentiation. This review will provide a summary of the most recent data regarding androgen-regulated target genes and modulation of androgen receptor activity, especially with regard to androgen-dependent and castration-recurrent prostate cancer.

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    ABSTRACT: BACKGROUND: Enzalutamide (formerly MDV3100 and available commercially as Xtandi®), a novel androgen receptor (AR) signaling inhibitor, blocks the growth of castration-resistant prostate cancer (CRPC) in cellular model systems and was shown in a clinical study to increase survival in patients with metastatic CRPC. Enzalutamide inhibits multiple steps of AR signaling: binding of androgens to AR, AR nuclear translocation, and association of AR with DNA. Here, we investigate the effects of enzalutamide on AR signaling, AR-dependent gene expression and cell apoptosis. METHODS: The expression of AR target gene prostate-specific antigen (PSA) was measured in LnCaP and C4-2 cells. AR nuclear translocation was assessed in HEK-293 cells stably transfected with AR-yellow fluorescent protein. The in vivo effects of enzalutamide were determined in a mouse xenograft model of CRPC. Differential gene expression in LNCaP cells was measured using Affymetrix human genome microarray technology. RESULTS: We found that unlike bicalutamide, enzalutamide lacked AR agonistic activity at effective doses and did not induce PSA expression or AR nuclear translocation. Additionally, it is more effective than bicalutamide at inhibiting agonist-induced AR nuclear translocation. Enzalutamide induced the regression of tumor volume in a CRPC xenograft model and apoptosis in AR-over-expressing prostate cancer cells. Finally, gene expression profiling in LNCaP cells indicated that enzalutamide opposes agonist-induced changes in genes involved in processes such as cell adhesion, angiogenesis, and apoptosis. CONCLUSIONS: These results indicate that enzalutamide efficiently inhibits AR signaling, and we suggest that its lack of AR agonist activity may be important for these effects. Prostate 9999: XX-XX, 2013. © 2013 Wiley Periodicals, Inc.
    The Prostate 06/2013; · 3.84 Impact Factor
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    ABSTRACT: The Androgen Receptor (AR) is a transcription factor that has a pivotal role in the occurrence and progression of prostate cancer (PCa). The AR is activated by androgens that bind to its ligand-binding domain (LBD), causing the transcription factor to enter the nucleus and interact with genes via its conserved DNA-binding domain (DBD). Treatment for PCa involves reducing androgen production or using anti-androgen drugs to block the interaction of hormones with the AR-LBD. Eventually the disease changes into a castration resistant form (CRPC) where LBD mutations render anti-androgens ineffective or where constitutively active AR splice variants, lacking the LBD, become over-expressed. Recently, we identified a surfaced exposed pocket on the AR-DBD as an alternative drug-target site for AR inhibition. Here, we demonstrate that small molecules designed to selectively bind the pocket effectively block transcriptional activity of full-length and splice variant AR forms at low- to sub- μM concentrations. The inhibition is lost when residues involved in drug interactions are mutated. Furthermore, the compounds did not impede nuclear localization of the AR and blocked interactions with chromatin, indicating the interference of DNA binding with the nuclear form of the transcription factor. Finally, we demonstrate the inhibition of gene expression and tumor volume in mouse xenografts. Our results indicate that the AR-DBD has a surface site that can be targeted to inhibit all forms of the AR, including Enzalutamide resistant and constitutively active splice variants and thus may serve as a potential avenue for the treatment of recurrent and metastatic prostate cancer.
    Journal of Biological Chemistry 08/2014; · 4.65 Impact Factor
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    ABSTRACT: Recently, deleted in breast cancer 1 (DBC1) has been suggested as a poor prognostic indicator of various human cancers and may possibly have a role as a coactivator of androgen receptor (AR). However, their roles in lymphoma are still unknown. We investigated the effect of the expression of DBC1 and AR in diffuse large B cell lymphoma (DLBCL). Immunohistochemical expression of DBC1 and AR were evaluated in 101 DLBCL samples by tissue microarray. Positive expression of DBC1 and AR was seen in 73% and 70% of DLBCL, respectively. In total DLBCL patients, DBC1 and AR expression were significantly associated with high clinical stage, elevated serum lactate dehydrogenase levels, and high international prognostic index scores, and they predicted shorter overall survival (OS) and relapse-free survival (RFS) by univariate analysis. DBC1 expression was also an independent prognostic indicator by multivariate analysis (OS, P = .017; RFS, P = .004). Especially, both DBC1 and AR expression significantly correlated with shorter OS and RFS in non-germinal center B cell (non-GCB)-type DLBCL by univariate analysis. In multivariate analysis, DBC1 expression was an independent prognostic predictor for OS (P = .035) and AR expression significantly correlated with RFS (P = .005). We demonstrate that the expression of DBC1 and AR are significant prognostic indicators for DLBCL patients, especially for unfavorable non-GCB-type DLBCL.
    Translational oncology 06/2013; 6(3):370-81. · 3.40 Impact Factor