By using a cre-lox conditional knockout strategy, we report here the generation of androgen receptor knockout (ARKO) mice. Phenotype analysis shows that ARKO male mice have a female-like appearance and body weight. Their testes are 80% smaller and serum testosterone concentrations are lower than in wild-type (wt) mice. Spermatogenesis is arrested at pachytene spermatocytes. The number and size of adipocytes are also different between the wt and ARKO mice. Cancellous bone volumes of ARKO male mice are reduced compared with wt littermates. In addition, we found the average number of pups per litter in homologous and heterozygous ARKO female mice is lower than in wt female mice, suggesting potential defects in female fertility and/or ovulation. The cre-lox ARKO mouse provides a much-needed in vivo animal model to study androgen functions in the selective androgen target tissues in female or male mice

ARTICLEMen have a substantially higher risk of bladder cancer than women ( 1 ). Excessive exposure of men to cigarette smoke and industrial chemicals, both of which include amines, has been suggested to result in the development of bladder cancer ( 2 ). However, sexrelated differences in the risk of bladder cancer have been shown to persist in the absence of exposure to known carcinogenic factors ( 2 ). In animal experimental models, males are more likely than females to develop bladder cancer induced by certain chemical carcinogens (e.g., aromatic amines, such as N -butyl-N -(4-hydroxybutyl) nitrosamine [BBN]) ( 3 ). In contrast, a recent study ( 4 ) showed that certain other carcinogens, such as the arsenical metabolite dimethylarsinic acid, are more toxic to the female bladder than the male bladder in rats. This finding is consistent with epidemiologic evidence suggesting that women are more susceptible to arsenic-induced bladder cancer than men ( 5 ). Thus, the basis for the sex-specific difference in bladder cancer incidence is not understood.A potential mediator of sex-specifi c differences is the androgen receptor (AR). The AR, a member of the nuclear receptor superfamily, is a ligand-dependent transcriptional factor that mediates the biologic effects of androgens ( 6 , 7 ). Expression of the AR has been detected in normal bladder epithelium ( 8 ) and in bladder carcinomas from both male and female patients ( 9 ). However, little is known about AR function in the bladder or about androgen metabolism in the bladder urothelium. Early studies ( 10 ) showed that levels of cytochrome P450 CYP4B1, which is present at higher levels in male bladder than female bladder and activates Affiliations of authors:

Overexpression of the HER2͞Neu protooncogene has been linked to the progression of breast cancer. Here we demonstrate that the growth of prostate cancer LNCaP cells can also be increased by the stable transfection of HER2͞Neu. Using AG879, a HER2͞Neu inhibitor, and PD98059, a MAP kinase inhibitor, as well as MAP kinase phosphatase-1 (MPK-1), in the transfection assay, we found that HER2͞Neu could induce prostate-specific antigen (PSA), a marker for the progression of prostate cancer, through the MAP kinase pathway at a low androgen level. Reporter assays and mammalian two-hybrid assays further suggest this HER2͞Neu-induced androgen receptor (AR) transactivation may function through the promotion of interaction between AR and AR coactivators, such as ARA70. Furthermore, we found this HER2͞Neu 3 MAP kinase 3 AR-ARAs 3 PSA pathway could not be blocked completely by hydroxyf lutamide, an antiandrogen used in the treatment of prostate cancer. Together, these data provide a novel pathway from HER2͞Neu to AR transactivation, and they may represent one of the reasons for the PSA re-elevation and hormone resistance during androgen ablation therapy in prostate cancer patients.

Androgens and the androgen receptor (AR) play important roles in male fertility, although the detailed mechanisms, particularly how androgen͞AR influences spermatogenesis in particular cell types, remain unclear. Using a Cre-Lox conditional knockout strategy, we generated a tissue-specific knockout mouse with the AR gene deleted only in Sertoli cells (S-AR ؊/y ). Phenotype analyses show the S-AR ؊/y mice were indistinguishable from WT AR mice (B6 AR ؉/y ) with the exception of testes, which were significantly atrophied. S-AR ؊/y mice were infertile, with spermatogenic arrest predominately at the diplotene premeiotic stage and almost no sperm detected in the epididymides. S-AR ؊/y mice also have lower serum testosterone concentrations and higher serum leuteinizing hormone concentrations than B6 AR ؉/y mice. Further mechanistic studies demonstrated that S-AR ؊/y mice have defects in the expression of anti-Mü llerian hormone, androgen-binding protein, cyclin A1, and sperm-1, which play important roles in the control of spermatogenesis and͞or steroidogenesis. Together, our Sertoli cell-specific AR knockout mice provide in vivo evidence of the need for functional AR in Sertoli cells to maintain normal spermatogenesis and testosterone production, and ensure normal male fertility. knockout mice ͉ anti-Mü llerian hormone ͉ testosterone