Comparison of Harvey ras and Kirstenras activity in rat mammary carcinogenesis

In cancers where mutations in the closely related Harvey ras, Kirsten ras, or N-ras genes are observed, one ras gene family member is often found mutated to the exclusion of other ras gene family members. Yet, the mechanism(s) responsible for tissue-selective ras gene mutations are not known. The overall goal of this thesis was to further characterize and evaluate the selective activation of the Harvey ras gene in the rat mammary carcinogenesis model. Three studies were performed in this thesis. The first study investigated ras gene activation in rats exposed to the carcinogen N-nitroso-N-methylurea (NMU) at different ages. A significant number of mammary carcinomas developed in rats exposed during both sexual development and senescence. Mutations in the Harvey ras gene were found in carcinomas from rats exposed to NMU during sexual development, but not those resulting from NMU exposure to senescent rats. No Kirsten ras gene mutations were found in mammary carcinomas from rats exposed to NMU at any age. In a second study, replication-defective retroviral vectors were used to express activated forms of the Harvey ras and Kirsten ras genes in rat mammary parenchyma. Although infection with the activated form of Kirsten ras led to the efficient development of rat mammary carcinomas, ten-fold higher numbers of mammary carcinomas were observed with the Harvey ras gene expressing vectors. In a third study, transgenic rats were produced that express the Harvey ras gene or the Kirsten ras gene controlled by the regulatory elements of the rat Harvey ras gene. Transgenic rats overexpressing Harvey Ras developed half as many tumors after NMU exposure as their non-transgenic littermates, whereas mammary carcinoma development was not significantly different in transgenic rats expressing the Kirsten ras gene driven by Harvey ras gene regulatory elements compared to their non-transgenic littermates. The collective results from these studies support a dominant role for Harvey ras in rat mammary carcinogenesis that is dependent on ras activity at the protein level.