Pathogenic characterization of 1-methyl-1-nitrosourea-induced mammary carcinomas in the rat

The induction of mammary carcinogenesis in the rat by 1-methyl-1-nitrosourea (MNU) is widely used in experimental breast cancer research. Inthe experiments reported, the Ha-ras codon 12 (ras12) mutation(GGA-->GAA) was used as a molecular marker to address issues of theclonality of carcinomas induced, pathogenetic independence among multiplecarcinomas within the same animal and topographic distribution of mutantras12 carcinomas in different mammary gland chains. In order to determinewhether the frequently observed morphologically distinguishable lobuleswithin carcinomas originate from the coalescence of independent lesions orwhether cancerous cells within a carcinoma share a common origin, 44randomly selected MNU-induced mammary carcinomas were genotyped for two tofour lobules each for the ras12 mutation. A total of 43 carcinomas out of44 (97.7%) had concordant ras12 genotypes among the multiple sites withineach tumor, which is consistent with the latter possibility. Next, it wasobserved that as carcinoma multiplicity increased, the discordance rate ofras12 genotypes among multiple carcinomas within the same animal increasedin a manner that was in excellent agreement with the expected discordancerate based on an assumption of no pathogenetic association amongcarcinomas. Furthermore, a significant difference was observed in theoccurrence of mutant ras12 carcinomas between the cervical-thoracic and theabdominal-inguinal mammary glands in that three times as many carcinomaswere mutant in the former as in the latter glands, whereas the occurrenceof wild-type carcinomas was approximately the same in both regions. Takentogether, the data are consistent with (i) carcinomas induced by MNU anddetected by palpation are monoclonal in origin, (ii)independently-initiated cells emerge as distinct mammary carcinomas in thesame animal, and (iii) the anatomical location of the gland may affect theprevalence of mammary carcinomas that harbor a mutant ras12.