World J Urol (2012) 30:279–285 the oncogenic transcription factor ERG under an AR responsive promoter causes profound changes: Reduction in AR expression, attenuation of AR activity at gene spe- ciﬁc loci, activation of NF-jB, and induced expression of epigenetic factors such as the methyltransferase EZH2 that in turn epigenetically silences differentiating factors and tumor suppressors, such as Nkx3.1 and DAB2IP [36, 37]. While a number of different fusions events between TMPRSS2 and ETS family members have been identiﬁed and implicated in the progression of PCa, TMPRSS2-ERG is the most common and has the biggest impact on prognosis. The luminal secretory epithelium is characterized, in part, by polarized orientation, cohesive extracellular interaction between like cells, and relative immobility of those cells in respect to the basal membrane. This pheno- type is maintained by adhesion molecules such as a- and b-catenin, which connect the actin cytoskeleton to intra- cellular domains of cadherins. Loss or down regulated of critical adhesion molecules enables cells to detach from their epithelial scaffold and move more freely within the extracellular matrix. When b-catenin translocates to the nucleus it can coactivate both AR and TCF/LEF tran- scription factors that induce epithelial to meshenchyme transition (EMT) markers Slug and Twist. Following cas- tration in mouse, PCa xenografts b-catenin relocated to the nuclei of LNCaP cells. Survival rates are signiﬁcantly shorter among PCa patients if b-catenin is not exclusively localized to the cell membrane and b-catenin expression is lost in metastasis [38, 39]. Multiple studies have shown that loss of E-cadherin expression and translocation of b-catenin from the leading edge of the cell to the nucleus accompanies the transition to a mesenchymal phenotype in vivo [40–42]. Although some controversy still exists con- cerning the incidence of EMT in cancer, the concept is supported by the observation of aberrant E-cadherin and b-catenin expression in metastatic PCas [40, 43]. Role of AR in development of castration-resistant prostate cancer (CRPC) Following the spread of PCas the standard of care is androgen ablation. Ablation is effective at ﬁrst, but PCa almost always recurs as CRPC, suggesting that inhibiting AR activity activates pro-survival mechanisms. While it is not known which mechanisms are activated in individual PCa patients, expression data implicates several key path- ways. As mentioned previously, castration elevates levels of TIF2 and p300, and ligand independent activators such as IL-6. In addition, one of the negative regulators of Akt action, INPP4B, is a direct AR target gene [44] and is likely lost during castration. Indeed, activation of Akt 283 signaling follows androgen ablation in men. In mouse models, activation of Akt can cause development of PIN even in the absence of AR signaling [45] while synergistic activation of Akt and AR is sufﬁcient to cause frank car- cinoma [46]. In addition, TMPRSS2-ERG fusion causes increased EZH2 signaling, associated with metastatic spread and recurrence. Conclusions The AR clearly represents a central hub in the regulation of normal prostate biology and the development, progression, therapeutic resistance and metastatic spread of PCa. Tar- geting the AR remains the central focus of PCa therapeu- tics and basic research. Despite this central role, therapeutic targeting of the AR has yet to prove fully successful. Our current and ever evolving understanding of the AR its cross-talk with intracellular signaling pathways and its compartmental functions will hopefully shed light on selective treatment targets. 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