The androgen receptor (AR) in syndromes of androgen insensitivity and in prostate cancer

The actions of androgens, principally testosterone and 5 alpha -dihydrotest osterone, are mediated by a specific receptor protein, the androgen recepto r (AR), which is encoded by a single-copy gene located on the human X-chrom osome. This receptor protein is a prototypical member of the nuclear recept or family and modulates a range of processes during embryogenesis and in th e adult. During embryogenesis, normal AR function is critical to the develo pment of the male phenotype and defects of the AR cause a range of phenotyp ic abnormalities of male sexual development. Complete loss of AR function h as been traced to a number of distinct types of genetic events, including a bnormalities of mRNA splicing, the introduction of premature termination co dons, and amino acid substitution mutations. An interesting subset of mutat ions is that in which the AR is completely undetectable using sensitive imm unoassays. In all instances, these functional abnormalities are associated with a phenotype of complete androgen insensitivity (complete testicular fe minization). By contrast, partial defects of AR function are almost invaria bly caused by amino acid substitutions within the DNA- and hormone-binding domains of the receptor protein. Such partial defects of receptor function may be caused by changes in either receptor function or receptor abundance. The alterations of AR function and expression that have been characterized in clinical prostatic cancers and in prostate cancer cell lines differ in s everal important respects. A number of studies have documented the emergenc e of considerable heterogeneity of AR expression at early stages in the dev elopment of prostate cancer. Despite these early changes of AR expression, a substantial body of information suggests that the AR is expressed in adva nced forms of prostate cancer, in some cases as the result of amplification events. While infrequent in localized tumors, mutations of the AR have bee n identified in a number of advanced prostatic cancers and in some instance s appear to alter the ligand specificity of the AR. Finally, it appears tha t other signaling pathways can act to influence AR function. (C) 2001 Elsev ier Science Ltd. All rights reserved.