The goal of this proposal is to understand how DNA repair processes protect tissues from multistage carcinogenesis. This focus is important to the understanding of spontaneous malignancy, malignancies induced by environmental or medicinal exposures and malignancies in cancer prone individuals such as those at risk for developing breast cancer due to the inheritance of an abnormal p53 gene, as occurs in the Li-Fraumeni syndrome. This study will bring together two disparate models of carcinogenesis: that of chemical carcinogenesis in which the role of DNA repair has recently been established and that of oncogene mediated cancers, in which the role of DNA repair is not clear. To perform these studies, a unique set of transgenic mice will be used. One set over expresses the DNA repair protein, O6-alkylguanine-DNA alkyltransferase and the other set carries one of four cancer-prone genes. The intent is to define the ability of increased levels of the DNA repair protein, O6- alkylguanine-DNA alkyltransferase to protect oncogene-initiated mice from both spontaneous and nitrosourea-induced thymic lymphomas. Previous studies have shown that transgenic mice which express very high levels of the alkyltransferase gene [MGMT] in thymus were remarkably protected from the development of methylnitrosourea [MNU]-induced thymic lymphomas compared to their non-transgenic littermates. These mice will be bred to mice which carry different genes associated with the development of spontaneous lymphomas. The four strains carry either the ttg-1 oncogene, the lck oncogene, the SV40 TAg or a knockout mutation of the p53 gene. Each is associated with a high rate of spontaneous lymphoma with a characteristic incidence and latency period. The genetic cross between these mice and the MGMT mice will be used to determine: a) whether DNA repair [specifically the alkyltransferase] is an important protective mechanism in the evolution of spontaneous malignancy in mice genetically predisposed to developing cancer [Specific Aim 1], b) whether chemical carcinogens [specifically, MNU] potentiate the effect of the genetic predisposition [Specific Aim 2], c) whether efficient DNA repair is capable of blocking this potentiation [Specific Aim 2] and d) whether MGMT expression can protect specific carcinogen target genes such as K-ras, p53 and myc [Specific Aim 3]. Bach of these has important implications for understanding the pathogenesis of human malignancy and for the development of potential genetic and other therapeutic programs involving MGMT for individuals carrying cancer prone genes such as, for instance, p53 mutations in Li-Fraumeni syndrome.
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