Mouse models of RB andp53 tumor suppressor pathways on development and carcinogenesis

Mouse models of human cancers involving inactivation of Rb and p53 genes have been established. Heterozygous Rb+/− mice are predisposed to tumors of neuroendocrine origins with complete penetrence, but no retinoblastomas were observed. Rb−/− embryos are not viable. Both heterozygous and homozygous p53 mutant mice are viable and are cancer-prone, but mammary carcinomas are rarely found in these mice.; To gain insights into how inactivation of the Rb pathway affects the developing retina we analyzed wild-type and Rb −/− embryonic retinas and retinal transplants and we established transgenic mice, TgIRBPE2F1, expressing human E2F1 in retinal photoreceptor cells under the regulation of the IRBP promoter. To understand processes involved in mammary caricinogeneis upon mutational inactivation of p53, we established mouse models with ma unary gland-specific inactivation of p53 gene.; A marked increase in cell proliferation and apoptosis was observed in the retinas of Rb−/− mice and TgIRBPE2F1 transgenic mice. In the transgenic mice, photoreceptor cells formed rosette-like arrangements at postnatal days 9 through 28. Complete loss of photoreceptors followed in the TgIRBPE2F1 mice but not in the Rb−/− retinal transplants.; Experimental mouse models were developed to study the role of p53 inactivation in the mammary epithelial cells in mammary carcinogenesis by tissue-specific inactivation of p53 using the Cre-loxP recombination system in p53fp /fpMMTVCre mice. In these mice, Cre-mediated excision of exons 5 and 6 deleted the DNA binding domain of p53. Mammary gland-restricted expression of Cre resulted in the formation of mammary tumors in 42 out of 43 mice by two years of age when the initial p53-deficient population of mammary epithelial and myoepithelial cells was less than 3%. Tumor latency was shortened to 6–14 months in mice containing an initial p53-deficient population of more than 20%, irrespective of pregnancy status.; To determine whether inactivation of Rb enhances p53-mediated mammary carcinogeneis, we have crossed Rb +/− mice with p53fp/ fpMMTVCre mice to generate p53fp/fpMMTVCre Rb+/− mice. The kinetics of carcinogenesis and molecular changes in mammary tumors from p53fp /fpMMTVCre Rb+/− mice will be characterized. (Abstract shortened by UMI.)...