Analysis of susceptibility of carcinogenesis using transgenic rats

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Taking the advantages of rat models characterized by larger organ size, abundant information regarding preneoplasias and virus-free constitution, we have concentrated attention on generation of transgenic rats bearing copies of the human c-Ha-ras proto-oncogene and shown the Hras 128 strain to be extremely sensitive to induction of mammary carcinomas, and to a lesser extent, lesions in the urinary bladder, esophagus and skin. In most of the mammary cancers, mutations of the transgene but not the endogenous H-ras gene are present, appearing to occur early in the process of carcinogenesis, which involves proliferation of cells in terminal end buds (TEBs) and intraductal hyperplasia before carcinomas arise. One of our recent studies demonstrated that mutation in the transgene occurred within 5 days after injection of N-methyl-N-nitrosourea and cancer development was observed within 30 days. Furthermore, while tumor development was independent of endogenous ovarian hormones, it was inhibited by soy isoflavones and promoted by atrazine and nonylphenols. Although further studies of mechanistic aspect are clearly necessary, the model appears to have great potential for screening purposes for modifying agents active in the mammary gland.