World J Urol (2012) 30:279–285 DOI 10.1007/s00345-011-0743-7 T O P I C P A P E R Androgen receptor footprint on the way to prostate cancer progression Myles C. Hodgson • Wayne A. Bowden • Irina U. Agoulnik Received: 16 June 2011 / Accepted: 27 July 2011 / Published online: 17 September 2011 The Author(s) 2011. This article is published with open access at Springerlink.com Abstract The prostate gland is exquisitely sensitive to androgen receptor (AR) signaling. AR signaling is oblig- atory for prostate development and changes in AR levels, its ligands or shifts in AR mode of action are reﬂected in the physiology of the prostate. The AR is intimately linked to prostate cancer biology through the regulation of epi- thelial proliferation, suppression of apoptosis and the development of castration-resistant disease. Thus, AR is the primary therapeutic target in various prostate diseases such as BPH and cancer. Although some tumors lose AR expression, most retain the AR and have elevated levels and/or shifts in activity that are required for tumor pro- gression and metastasis. New AR inhibitors currently in clinical trials with higher receptor afﬁnity and speciﬁcity may improve prostate cancer patient outcome. Several events play an important role in initiation, primary tumor development and metastatic spread. Androgen receptor activity and promoter speciﬁcity change due to altered coregulator expression. Changes in epigenetic surveillance alter the AR cistrome. Both systemic and local inﬂamma- tion increases with PCa progression affecting AR levels, activity, and requirement for ligand. Our current under- standing of AR biology suggest that global androgen sup- pression may drive the development of castration-resistant disease and therefore the question remains: Does effective inhibition of AR activity mark the end of the road for PCa or only a sharp turn toward a different type of malignancy? Keywords Androgen receptor Prostate cancer Castration resistance Metastasis M. C. Hodgson W. A. Bowden I. U. Agoulnik (&) Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA e-mail: iagoulnik@ﬁu.edu Introduction Prostate cancer (PCa) originates in the epithelial compart- ment of the prostate, an organ dependent on androgen receptor (AR) signaling for its development, maintenance and physiological function. It is not clear which early oncogenic events lead to neoplastic transformation, but due to the heterogeneity of PCa there are likely numerous ini- tiating factors. While there is some hereditary component associated with PCa incidence, the major risk factor for the development of this malignancy is age. Two major hall- marks of aging in men are decreasing levels of testosterone and elevated levels of inﬂammatory cytokines, including interleukin-6 (IL-6). Systemic inﬂammation suppresses testosterone secretion and testosterone supplementation has been shown to reduce the levels of inﬂammatory cytokines in hypogonadal men [1]. On the other hand, IL-6 can acti- vate AR at suboptimal levels of androgens and indepen- dently of its ligands potentially causing a shift in the AR cistrome and transcriptome. Analysis of 218 PCas demon- strated that the AR pathway is activated in 56% of primary and 100% of metastatic PCas [2]. Thus, it is plausible that AR is a key or at the very least an obligatory accessory protein in PCa initiation and its function continuously changes with progression. Dramatic changes occur in a variety of cell signaling processes with PCa progression (Fig. 1). In this review, we will limit our discussion to changes in AR function observed in PCa patients and mechanistically substantiated in cell lines or mouse models. Primary tumors In the normal prostate, AR is expressed in both epithelial and stromal compartments as well as in endothelial cells. 123