Prostatic neoplasia in transgenic mice with prostate-directed overexpression of the c-myc oncoprotein

BACKGROUND. Promoter elements within the 5' DNA region of the rat C(3)1 gen e have been shown to direct prostate-specific expression of gene products w hen they are fused through recombinant DNA procedures and used to produce t ransgenic mice. In order to test the in vivo effects of chronic overexpress ion of the mouse c-myc protooncogene on the prostate glands of transgenic m ice, we created several lines of C(3)1-c-myc transgenic mice and then exami ned the phenotype of males with this genetic alteration. METHODS. The modified promoter and 5' region of the rat C(3)1 gene was fuse d to the coding region of the mouse c-myc gene using recombinant DNA techni ques. This DNA was used to create three different founder Lines of transgen ic mice. Tissues from males and females heterozygous for the transgene were examined for expression of the recombinant mouse c-myc mRNA by an RNase pr otection assay. Prostates from males were examined for expression of recomb inant c-myc mRNA by in situ hybridization. Thin sections of fixed ventral p rostates from males were analyzed by microscopy for histological abnormalit ies. RESULTS. Three different Lines of transgenic mice were obtained from these procedures. These mice demonstrated expression of recombinant mouse c-myc m RNA in the testis and ventral prostates of males and in the uterus of femal es. In situ hybridization demonstrated that the epithelial cells were the s ource of recombinant c-myc expression in the ventral prostates of the trans genic lines. Microscopic analysis of the ventral prostates from these mice demonstrated abnormalities in epithelial cell morphology seemingly typical of an intraepithelial neoplasia-like phenotype. However, none of the males of any of the lines developed overt prostatic adenocarcinoma over their lif etimes. CONCLUSIONS. Chronic overexpression of c-myc in the ventral prostate epithe lial cells of C3(1)-c-myc transgenic mice leads to the development of epith elial cell abnormalities similar to those seen in low-grade prostatic intra epithelial neoplasia in humans. These abnormalities were not found to progr ess to adenocarcinoma over the lifetimes of the transgenic mice, suggesting the need for additional oncogenic changes in the pathway to prostatic aden ocarcinomas. Furthermore, our cumulative experience with the use of the C3( 1) gene promoter in the generation of transgenic mice suggests that the pro basin promoter element provides a much more specific and effective means to target transgenes to the prostate glands of mice. (C) 2000 Wiley-Liss, Inc .