N-ETHYL-N-NITROSOUREA INDUCES MAMMARY CANCERS IN THE PITUITARY-ISOGRAFTED MOUSE WHICH ARE HISTOLOGICALLY AND GENOTYPICALLY DISTINCT FROM THOSE INDUCED BY N-METHYL-N-NITROSOUREA

N-Ethyl-N-nitrosourea (ENU) and N-methyl-N-nitrosourea (MNU) are alkyl ating agents which respectively ethylate or methylate nucleophilic cen ters in the cell such as DNA. In vitro studies with naked DNA and bact erial mutagenesis assays suggest that these two compounds induce diffe rent spectra of genetic lesions. In addition, the ethyl-DNA adducts in duced by ENU persist longer than the methyl-DNA adducts induced by MNU . Since MNU is a known mammary carcinogen in the pituitary-isografted mouse, these data suggest that ENU may be an even more potent carcinog en than MNU. The purpose of this study was to determine whether ENU wa s a mammary carcinogen in the pituitary-isografted mouse and if so, to compare the genotype and phenotype of ENU-induced mammary tumors with those induced by MNU. Fifteen adult female virgin BALB/c mice were is ografted with two pituitaries and subsequently treated with a single i ntravenous injection of ENU (50 mu g/g body weight). Mammary adenocarc inomas arose in all of the survivors (n = 12) with a median latency of 27 weeks and a mean frequency of 1.4 cancers per mouse. When tumor DN A was analyzed for mutations in the 12th and 61st codons of c-Ki-ras o r c-Ha-ras protooncogenes, only wild type sequences were found. This i s in contrast to MNU which causes a G to A transition mutation in the 12th codon of the c-Ha-ras proto-oncogene in about one of five mammary cancers induced in pituitary-isografted mice. Furthermore, the ENU-in duced tumors were solid viable papillary adenocarcinomas, whereas MNU induced tumors are highly necrotic adenocarcinomas with squamous metap lasia. These results demonstrate that, in the pituitary-isografted mou se, ENU is as potent a mammary carcinogen as MNU and suggest that onco genes other than c-Ki-ras or c-Ha-ras may be involved in ENU-induced m ammary cancers.