Altered expression of transforming growth factor betas during urethral and bulbourethral gland tumor progression in transgenic mice carrying the androgen-responsive C3(1) 5' flanking region fused to SV40 large T antigen

We demonstrate that targeted expression of SV40 large T antigen (TAg) tothe urethral (periurethral) and bulbourethral gland epithelium leads toadenocarcinoma formation in these tissues after 7 months of age, which areextremely rare sites for spontaneous tumor formation in humans. Thedevelopment of proliferative lesions in the urethral gland predictablyfollows a temporal course of progression with approximately one third ofmale animals developing urethral tumors by 1 year of age. Tumor progressionin these organs correlates to the level of TAg and p53 expression.Immunoprecipitation confirmed that SV40 TAg protein was bound to p53 and Rbp110 in vivo. Expression of transforming growth factor beta (TGFbetas) wasevaluated during tumor progression of urethral gland carcinomas. Elevationsof intracellular and extracellular TGFbeta1 and extracellular TGFbeta3 werefound in preneoplastic and neoplastic lesions, suggesting that increasedTGFbetas may augment tumor growth. c-Met expression showed a tendency forincreased expression in the urethral gland carcinomas. We speculate thatthe directed expression of SV40 TAg by the hormone responsive C3(1) geneand subsequent tumor formation in these organs is influenced by androgens,since these tissues and carcinomas express androgen receptor (AR) and ariseonly in male transgenic mice. Several cell lines established from theurethral carcinomas were also shown to express AR, but are not androgendependent in culture. To our knowledge, this is the first transgenic animalmodel for urethral and bulbourethral carcinomas. This transgenic mousemodel and the cell lines derived from it may provide a unique opportunityfor dissecting molecular mechanisms involved in the tumorigenesis of theseorgans which otherwise rarely develop cancer.