Developmental studies of the prostate have established that ductal morphogenesis, epithelial cytodifferentiation, and proliferation/apoptosis are regulated by androgens acting through stromal androgen receptor (AR). Here, we found mice lacking epithelial AR within the mature prostate (pes-ARKO) developed prostate tissue that was less differentiated and hyperproliferative relative to WT littermates. Epithelial AR protein was significantly decreased in 6-week-old mice and was nearly absent by ≥24 weeks of age. Circulating levels of testosterone, external genitalia, or fertility were not altered in pes-ARKO mice. A significant ( P < 0.05) increase in bromo-deoxyuridine-positive epithelia was observed in ventral and dorsal-lateral prostates of pes-ARKO mice at 24 weeks of age. Less differentiation was observed as indicated by decreased epithelial height and glandular infolding through 24 weeks of age, differentiation markers probasin, PSP-94, and Nkx3.1 were sig nificantly decreased, and epithelial sloughing and luminal cell apoptosis increased from 6 to 32 weeks of age in pes-ARKO mice. Gain of function occurred by crossing pes-ARKO to the T857A transgenic mice containing constitutively activated AR. In T857A-pes-ARKO mice prostates were of normal size, contained glandular infoldings, and maintained high secretory epithelium, and the appropriate prostatic epithelial proliferation was restored. Collectively, these results suggest that prostatic epithelial AR plays an important role in the homeostasis of the prostate gland. These data support the hypothesis that epithelial AR controls prostate growth by suppressing epithelial proliferation in the mature gland.

To differentiate roles of androgen receptor (AR) in prostate stromal and epithelial cells, we have generated inducible-(ind)ARKO-TRAMP and prostate epithelial-specific ARKO TRAMP (pes-ARKO-TRAMP) mouse models, in which the AR was knocked down in both prostate epithelium and stroma or was knocked out in the prostate epithelium, respectively. We found that loss of AR in both mouse models resulted in poorly differentiated androgen deprivation therapy ͉ testosterone ͉ TRAMP

We concluded that both PSA nadir and time to PSA nadir are significant predictors of disease progression for prostate cancer patients receiving ADT.

Recent genomewide association studies have identified several prostate cancer susceptibility variants. However, the association between these variants and biochemical failure in prostate cancer patients receiving radical prostatectomy has not been determined. We systematically evaluated 20 prostate cancer-associated single-nucleotide polymorphisms in a cohort of 320 localized prostate cancer patients receiving radical prostatectomy. Each single-nucleotide polymorphism found to be associated with the recurrence of prostate-specific antigen was further analyzed by Kaplan-Meier analysis and Cox regression model. Three prostate cancer susceptibility single-nucleotide polymorphisms (rs1447295 at 8q24, rs7920517 and rs10993994 at 10q11) were associated with prostate-specific antigen recurrence (P < 0.02). Of these, rs7920517 and rs10993994, which were in strong linkage disequilibrium (r 2 = 0.91), also showed significant associations with poor prostate-specific antigen-free survival following radical prostatectomy (log-rank test; P < 0.01). The associations remained significant in our multivariate Cox proportional hazards analysis after adjusting for other clinicopathologic risk covariates (P < 0.01). In conclusion, loci associated with risk for prostate cancer, such as rs7920517 and rs10993994, might also be used to predict the recurrence of prostate-specific antigen in prostate cancer patients receiving radical prostatectomy.

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Recent studies have shown that docetaxel-based chemotherapy confers a survival benefit in patients with castration-resistant prostate cancer (PC). Also epidermal growth factor receptor (EGFR) was found to have multiple roles in prostatic tumorigenesis. However, the EGFR-mediated chemoresistance mechanism in human PC was not well delineated. In this study, we explored the mechanism of EGFR-mediated docetaxel resistance in PC. A series of stable docetaxel-resistant PC/DX sublines were established at our laboratory. The docetaxel IC50s of PC3 and PC/DX25 cells were 0.01 and 1.33 μM, respectively. Cellular resistance to docetaxel was significantly associated with increased EGFR and EGFR activation in PC/DX25. There was a dose-dependent increase in EGFR expression associated with the magnitude of docetaxel resistance. Expression of EGFR in PC/DX25 was higher than that in PC3, RWPE-1 and LNCaP cells. Similar results were also found in human PC tissues by immunohistochemical staining. We showed that docetaxel sensitivity can be stored in PC/DX25 cells by knockdown and inactivation of EGFR expression through EGFR siRNA and specific inhibitors, respectively. Contrarily, overexpression of EGFR or recombinant EGF protein treatment could rescue PC3 cells from docetaxel-mediated cytotoxicity. Gefitninb (ZD1839) significantly inhibited the growth of PC/DX25 cells by MTT in vitro and on xenografted nude mice in vivo. Moreover, EGFR-mediated docetaxel resistance occurred through the Akt-dependent ABCB1 expression in PC cells. These findings demonstrated EGFR played an important role in docetaxel-resistant PC and EGFR inhibition may enhance the therapeutic efficacy of docetaxel-based treatment.

This study is the first to recognize the prognostic significance of common deletions in steroid inactivation pathways in localized PCa after RP. Alteration of circulating steroid levels associated with UGT2B gene deletions further support the notion that such inherited genomic deletions have the potential to modify hormonal exposure and risk of recurrence.

Purpose: Recent evidence indicates that small noncoding RNA molecules, known as microRNAs (miRNAs), are involved in cancer initiation and progression. We hypothesized that genetic variations in miRNAs and miRNA target sites could be associated with the efficacy of androgen-deprivation therapy (ADT) in men with prostate cancer.Experimental Design: We systematically evaluated 61 common single nucleotide polymorphisms (SNPs) inside miRNAs and miRNA target sites in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan-Meier analysis and Cox regression model.Results: Four, seven, and four SNPs were significantly associated with disease progression, PCSM, and ACM, respectively, after ADT in univariate analysis. KIF3C rs6728684, CDON rs3737336, and IFI30 rs1045747 genotypes remained as significant predictors for disease progression; KIF3C rs6728684, PALLD rs1071738, GABRA1 rs998754, and SYT9 rs4351800 remained as significant predictors for PCSM; and SYT9 rs4351800 remained as a significant predictor for ACM in multivariate models that included clinicopathologic predictors. Moreover, strong combined genotype effects on disease progression and PCSM were also observed. Patients with a greater number of unfavorable genotypes had a shorter time to progression and worse prostate cancer-specific survival during ADT (P for trend < 0.001).Conclusion: SNPs inside miRNAs and miRNA target sites have a potential value to improve outcome prediction in prostate cancer patients receiving ADT.