World J Urol (2012) 30:279–285 [8]. A modest but highly signiﬁcant reduction in FOXA1 mRNA expression in two PCa cohorts is signiﬁcantly associated with metastatic PCa and poor prognosis [8]. High nuclear accumulation of FOXA1 protein is also associated with metastatic disease [9]. Thus, changes in FOXA1 expression and distribution may change the AR cistrome and consequentially its function, which is fre- quently observed during the progression of PCa. AR activity AR activity can be altered through a number of different mechanisms: receptor mutations, alternative splicing of AR mRNA, changes in the levels of coactivator and core- pressors, and activation of cell signaling pathways (Fig. 1). Mutations and splicing A signiﬁcant portion of PCas bear somatic mutations of AR that affect its ligand speciﬁcity, interaction with coregula- tors, dimerization, stability, and other AR properties [10]. In a mouse model, expression of an AR E231G mutant that has altered coregulator interactions caused rapid develop- ment of metastatic PCa with 100% penetrance [11]. AR splice variants (ARV), which typically lack the ligand binding domain of the receptor and do not require agonist for activity, were ﬁrst identiﬁed in CWR22R PCa cells and subsequently PCa specimens. Expression of these variants is often induced by castration and associated with tumor progression to CRPC [12]. Elevated ARV levels have been observed in patients who failed hormone therapies pro- viding survival and growth advantage by acting coopera- tively with full length AR [13]. In in vitro and xenograft models, various ARVs confer both resistance to castration associated tumor atrophy and promote growth in androgen- depleted conditions [14]. Elevated ARV expression potentially disturbs cell cycle regulation and creates a shift in the AR transcriptome [14, 15]. FOXA1 directly interacts with the AR through the hinge region, which is lost or altered in many ARVs. Therefore, some mutants and splice variants may provide a survival and growth advantage in androgen-depleted conditions by shifting the AR tran- scriptome via circumventing FOXA1 regulation of AR genomic targeting [8]. Cell Cycle Androgens promote proliferation through signals that modulate critical regulators of the cell cycle. For the most part, the AR regulates the cell cycle through induction of signals that regulate G1-S phase transition through the promotion of G1 cyclin-dependant kinases (CDKs) and inhibition of the retinoblastoma (Rb) tumor suppressor 281 gene [16]. Androgens also regulate the transcription and turnover of the cell cycle regulators p21Cip1 and p27Kip1. The M-phase checkpoint protein UBE2C, a direct target of the AR, is signiﬁcantly overexpressed in CRPC. In addi- tion, AR displays ligand independent recruitment to the UBE2C loci in ablation-resistant PCa cell lines concurrent with elevated UBE2C expression [17]. Coactivators Coregulators are integral to the normal function of steroid receptors and the development and progression of a wide spectrum of human diseases [18]. AR coregulators stimu- late or decrease AR activity in a promoter speciﬁc manner [19]. Therefore, changes in particular coregulator expres- sion and regulation will have distinct effects on AR target genes and the AR transcriptome. AR is potentiated by the p160 family of coactivators that include SRC-1 (NCOA1), TIF2 (NCOA2), and SRC-3 (AIB1, NCOA3). In the normal prostate, SRC-1 expression is uniform throughout the prostate but varies considerably between men. Levels of SRC-1 do not change with the development of PCa but men that have higher SRC-1 expression will develop more aggressive PCas [20]. TIF2 expression in normal prostate is low to undetectable. With primary PCa, development expression of TIF2 increases from low to high-grade tumors and recurrent CRPCs have the highest uniformed expression of TIF2 [21]. The AR directly binds to the TIF2 promoter and an intron and represses TIF2 expression. Reduced androgen levels increase TIF2 expression and it becomes available to potentiate AR and other transcription factors stimulating both AR dependent and AR independent proliferation [21]. Thus, androgen ablation itself may cause increased TIF2 expression and contribute to the development of CRPC. The TIF2 gene is positioned at 8q13.3 in close proximity to MYC at 8q24.21; these regions are most frequently ampliﬁed in PCa [2]. Con- sistent with our protein expression studies, Taylor et al. found positive copy number alterations through ampliﬁ- cation and overexpression of TIF2 in 8% of primary tumors and 37% of metastases [2]. Signiﬁcantly, primary tumors with ampliﬁcation of TIF2 display an increase in AR signaling [2]. SRC-3 expression is similar throughout the same prostate but varies greatly between patients [22]. Similar to SRC-1, elevated levels of SRC-3 in normal prostate is a predictor of the development of more aggressive PCa but its expression is signiﬁcantly increased with the development of primary tumors [22]. In addition to activating AR transcriptional activity, SRC-3 coactivates AP1 and PEA3 transcription factors [23]. Akt is a direct transcriptional target of AP1 and increased SRC-3 expression increases total and phospho-Akt levels; 123