ROLE OF RAS ONCOGENES IN CHEMICAL CARCINOGENESIS

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Carcinogen-induced animal tumor model systems, in which specific oncogenes are found to be reproducibly activated, are providing a means of understanding the role of oncogene activation in neoplasia. We have found activated H-ras-1 oncogenes in mammary carcinomas of rats induced by a single administration of the direct acting carcinogen, N-nitroso N'- methylurea (NMU), during puberty. Activation of each of the H-ras-1 oncogenes was caused by a G to A transition, the known mode of action of NMU. These results represented the first identification of a biologically revelant gene as a target of carcinogen and implicated ras oncogenes in the initiation of carcinogenesis. In order to separate, temporally, the cancer-initiating event, presumed to be activation of the oncogene, and the promotional role played by sexual hormones, we examined tumors induced by neonatal, rather than pubertal exposure of rats to NMU. With this protocol, 50% of mammary tumors that arose following puberty contained G to A activated H-ras-1 oncogenes. In contrast, close to 90% of kidney tumors contained G to A activated K-ras-2 oncogenes. These data again provide strong but only circumstantial evidence for ras oncogene involvement in initiation of carcinogenesis. Using the polymerase chain reaction (PCR) technique, we intend to look for activated ras oncogenes in cells of the mammary gland and kidney before the appearance of a detectable neoplasm, and to determine if activated ras oncogenes exist in other tissues that never develop tumors. We will also address the role of active cell division in the expression of malignantly activated, but quiescent ras oncogenes, such as in regenerating liver. Lastly, we will explore the usefulness of immunohistochemistry with antibodies specific for activated ras p21 proteins with single amino acid substitutions, to study the origin and stages of development of the kidney tumors.