280 World J Urol (2012) 30:279–285 Fig. 1 Alterations in AR function in PCa and the development of CRPC. Classical ligand-dependent AR action and interplay between various intracellular signaling pathways in primary tumors (Left). Following androgen ablation, increased AR levels and a dramatic shift in AR function is observed ultimately leading to the develop- ment of CRPC (Right). Red boxes and arrows indicate increased AR is a transcription factor that can be activated by a wide range of natural ligands such as testosterone, dihydrotes- tosterone, estradiol, as well as independently of ligand by inﬂammatory and growth hormone receptor pathways. Upon activation, AR binds to androgen response elements (AREs) in the promoter, enhancer and intronic regions of androgen regulated genes frequently guided by pioneer factors [3]. Once bound to regulatory regions, AR assem- bles a complex of coregulators that modify chromatin, general transcription machinery, and other proteins that regulate transcription [3]. During PCa progression both AR activity and target gene speciﬁcity change causing a shift in AR function from pro-differentiation to pro-proliferation. AR levels AR expression in primary tumors correlates signiﬁcantly with an increased proliferative index and markers of aggressive disease and patients with higher levels of AR recur and ultimately die of PCa signiﬁcantly faster [4, 5]. Using mouse xenograft models, Chen et al. monitored changes associated with the development of castration resistance in seven independently derived androgen dependent PCa cell lines. Remarkably, they found a single consistent change, increased expression and protein levels 123 levels and/or activation of signaling pathways. Green boxes denote factors that are lost during the progression of PCa. The TMPRSS2- ERG fusion event is present in 60% of PCas and is indicated by the dashed lines. Dotted lines indicate cross talk with the AR of AR [6]. Overexpression of AR in PCa cells stimulated proliferation at suboptimal levels of androgens and helped overcome the inhibitory effect of bicalutamide [6]. However, overexpression of wild-type AR in luminal epithelial cells of the mouse caused high-grade prostatic intraepithelial neoplasia (PIN), without the development of overt carcinoma [7], suggesting that for PCa develop- ment both elevated AR levels and changes in activity are required. AR Cistrome AR binding sites on the chromatin are collectively called the AR cistrome. These sites are frequently marked by speciﬁc chromatin modiﬁcations introduced by pioneer factors such as OCT1, GATA2 and FOXA1 prior to hor- mone treatment. In LNCaP cells over half of the AR binding loci are also bound by FOXA1. On most of these sites, FOXA1 binds before hormone treatment and AR recruitment. Interestingly, FOXA1 ablation causes massive reprogramming of the AR cistrome: 40% of loci are pre- served with increased level of AR recruitment, the remaining 60% of loci are lost, and many new AR binding sites appear, causing the AR cistrome to increase more than fourfold with corresponding changes in gene expression