PROGRESSION OF PROSTATIC INTRAEPITHELIAL NEOPLASIA TO INVASIVE-CARCINOMA IN C3(1) SV40 LARGE T-ANTIGEN TRANSGENIC MICE - HISTOPATHOLOGICAL AND MOLECULAR BIOLOGICAL ALTERATIONS/

The progression of prostatic intraepithelial neoplasia (PIN) to invasi ve prostate carcinoma has been analyzed in the C3(1)T-AG transgenic mo use model and appears very similar to the process proposed to occur in humans, PIN lesions in these transgenic mice histologically resemble those found in human PIN, Low-grade PIN was observed in the ventral an d dorsolateral lobes at 2 months of age, whereas high-grade PIN was fo und in both lobes by 5 months of age, A progressive increase in the nu mber of PIN lesions was observed with age. Prostate carcinomas, which appeared to arise from PIN lesions, mere found by 7 months of age in t he venll al lobe and 11 months of age in the dorsolateral lobe. Expres sion of T-AG mRNA and protein in these lesions correlated with the dev elopment of PIN and carcinomas, as did the overexpression of p53 prote in, Apoptosis levels were quite low in normal epithelial cells, modera te in low grade PLY, and high in high-grade PIN and carcinomas. Levels of expression of proliferating cell nuclear antigen correlated with t he degree of severity of the prostate lesions. Eighteen % of PIN lesio ns were found to already; harbor Ha-ras mutations, whereas 33% of carc inomas showed various mutations in Ha-ras, Ki-ras, and/or p53. Mutatio ns in Ha-ras may, there fore, be an early event in a significant porti on of PIN lesions, Because high-grade PIN showed many characteristics similar to those observed in carcinomas and high-grade PIN was often f ound contiguous to carcinomas, we conclude that high-grade PIN is a pr ecursor lesion of prostate carcinoma in this transgenic model. These t ransgenic mice will be useful to study mechanisms responsible for the progression of invasive carcinomas from PIN precursor lesions, as may occur during the development of prostate cancer in humans.