ras gene mutations are absent in NMU-induced mammary carcinomas from aging rats

Carcinoma induction in the rat mammary carcinogenesis model is age dependent. In this study, mammary cancer susceptibility and ras gene activation were investigated in rats exposed to N:-methyl-N:-nitrosourea (NMU) at 2, 6, 8 and 15 months. Animals were resistant to NMU-induced mammary tumor development when exposed at 6 and 8 months of age, whereas a significant number of mammary carcinomas developed in animals exposed to NMU at 2 and 15 months of age. G35-->A35 activating mutations in the Harvey ras gene were found only in mammary carcinomas from rats exposed to NMU at 2 months of age, but not in tumors that developed in animals exposed to NMU at 15 months of age. No G35-->A35 activating mutations were present in the Kirsten ras gene of any of the mammary tumors. Additional analysis of exons 1 and 2 of the Harvey ras gene from mammary carcinomas that developed in animals exposed to NMU at 15 months of age did not reveal any other activating mutations in this gene. In mammary carcinomas from animals exposed to NMU at 2 months of age, the frequency of mammary carcinomas with mutations in the Harvey ras gene was independent of the time from which the tumor first appeared. Therefore, age at the time of carcinogen exposure plays a critical role in both breast cancer susceptibility and the molecular events that contribute to mammary carcinoma development.