Since the original observations of Huggins and Hodges that prostate cancers are androgen dependent, androgen ablation therapy has been the gold standard for the treatment of advanced prostate cancer (CaP). Androgen receptor (AR) is believed to play critical roles in the development and progression of CaP. Treatment for neoadjuvant, adjuvant and recurrent disease all center on the regulation and manipulation of the androgen pathway, in which AR plays an integral role. Recent discoveries that frequent overexpression of ETS-related proto-oncogenes may be driven by AR as a consequence of common genomic rearrangements can hold the key towards the understanding of early phases of prostate cancer. Furthermore, AR function evolves as the cell changes towards a clinically androgen depletion independent state. Comprehension of AR function, regulation and abnormalities are increasingly refined towards the understanding of the role of AR in CaP, and in therapeutic applications. Development of future therapy for CaP will be aided by improving the knowledge of dysfunctions of AR and its network in prostate cancer. This review focuses salient features of AR and on the recent advances addressing AR dysfunctions in prostate cancer.

ACKnOwLEDgEMEnTSSee page 109. AbbREviATiOnSPMEPA1, transmembrane, prostate androgen induced RNA; STAG1, solid tumorassociated protein 1; AR, androgen receptor; ARE, androgen responsive element; NKX3.1, NK3 transcription factor related, locus 1; KLK3/PSA, kallikrein 3/prostate specific antigen; GSTP1, glutathione S-transferase pi; TGFβ, transforming growth factor beta; DNMTs, DNA methyl transferases; GAPDH, glyceraldehyde-phosphate dehydrogenase; HES-1, hairy and enhancer-of-split; ROAZ, zinc finger protein 423 AbSTRACTA cascade of epigenetic events contributes to the selective growth advantage of cancer cells during tumor progression. PMEPA1 gene is an androgen-inducible negative regulator of cell growth in the prostate epithelium. During prostate cancer progression PMEPA1 gene transcription is reduced or lost prompting us to investigate the role of epigenetic events in this process. In LAPC4 cells harboring wild type androgen receptor decitabine (5-aza-2'-deoxycitidine) treatment resulted in increased expression of PMEPA1 along with other androgen-inducible genes, suggesting a role for DNA methylation in the repression of androgenic cell growth control signals in prostate cancer. In contrast, mutant androgen receptor expressing LNCaP cells were deficient in this response. Therefore, decitabine-induced expression of cell growth controlling genes such as NKX3.1 or PMEPA1 underlines the clinical applicability of decitabine in prostate tumors harboring wild type androgen receptor. Further analysis of DNA methylation within the PMEPA1 promoter downstream sequences suggests that methylation of SP1 binding sites may also contribute to the repression of PMEPA1 gene.

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