Lack of effect of human c-Ha-ras proto-oncogene overexpression on prostate carcinogenesis in probasin/SV40 T antigen transgenic rats.

We have previously reported that transgenic (Tg) rats bearing the SV40 T antigen under probasin promoter control (PB/SV40T) develop prostate carcinomas at 100% incidence, showing their prostate carcinoma growth to be completely androgen-dependent. Transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are also highly susceptible to carcinogen induction of multiple mammary carcinomas, in this case estrogen-independent, since ovariectomy does not affect mammary tumor formation. A relationship between ras/mitogen-activated protein kinase signaling and androgen responsiveness of prostate cancer cells has been reported. Therefore it is of interest to investigate whether expression of human c-Ha-ras affects the androgen-dependence of prostate carcinomas developing in the PB/SV40T Tg rat. For this purpose, we established double transgenic (rasTag) rats bearing both PB/SV40T and Hras128. In prostate tissues of the rasTag rats, expression of both human c-Ha-ras and SV40T was confirmed, but the prostate tumor incidence and growth were not significantly affected. Castration at 15 weeks of age induced complete tumor involution in the rasTag rats. These results indicate that the human c-Ha-ras proto-oncogene product does not influence the androgen-dependence of prostate carcinogenesis due to the probasin-mediated SV40 T antigen, despite the estrogen-independence of mammary carcinogenesis in Hras128 rats.