title: Mutation of the androgen receptor causes oncogenic transformation of the prostate.
abstract: Recent evidence demonstrates that the androgen receptor (AR) continues to influence prostate cancer growth despite medical therapies that reduce circulating androgen ligands to castrate levels and/or block ligand binding. Whereas the mutation, amplification, overexpression of AR, or cross-talk between AR and other growth factor pathways may explain the failure of androgen ablation therapies in some cases, there is little evidence supporting a causal role between AR and prostate cancer. In this study, we functionally and directly address the role whereby AR contributes to spontaneous cancer progression by generating transgenic mice expressing (i) AR-WT to recapitulate increased AR levels and ligand sensitivity, (ii) AR-T857A to represent a promiscuous AR ligand response, and (iii) AR-E231G to model altered AR function. Whereas transgenes encoding either AR-WT or AR-T857A did not cause prostate cancer when expressed at equivalent levels, expression of AR-E231G, which carries a mutation in the most highly conserved signature motif of the NH2-terminal domain that also influences interactions with cellular coregulators, caused rapid development of prostatic intraepithelial neoplasia that progressed to invasive and metastatic disease in 100% of mice examined. Taken together, our data now demonstrate the oncogenic potential of steroid receptors and implicate altered AR function and receptor coregulator interaction as critical determinants of prostate cancer initiation, invasion, and metastasis.
authors.affiliation: Department of Molecular and Cellular Biology, Pathology, and Urology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Guangzhou
authors.initials: G
authors.lastname: Han
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Harris
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yu
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: Demayo
authors.forename: Wayne
authors.initials: W
authors.lastname: Tilley
authors.forename: Norman M
authors.initials: NM
authors.lastname: Greenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D011471:Prostatic Neoplasms / Q000209:etiology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D011944:Receptors, Androgen