PATHOGENETIC CHARACTERIZATION OF 1-METHYL-1-NITROSOUREA-INDUCED MAMMARY CARCINOMAS IN THE RAT

The induction of mammary carcinogenesis in the rat by 1-methyl-1-nitro sourea (MNU) is widely used in experimental breast cancer research, In the experiments reported, the Ha-ras codon 12 (ras12) mutation (GGA - -> GAA) was used as a molecular marker to address issues of the clonal ity of carcinomas induced, pathogenetic independence among multiple ca rcinomas within the same animal and topographic distribution of mutant ras12 carcinomas in different mammary gland chains, In order to deter mine whether the frequently observed morphologically distinguishable l obules within carcinomas originate from the coalescence of independent lesions or whether cancerous cells within a carcinoma share a common origin, 44 randomly selected MNU-induced mammary carcinomas were genot yped for two to four lobules each for the ras12 mutation, A total of 4 3 carcinomas out of 44 (97.7%) had concordant ras12 genotypes among th e multiple sites within each tumor, which is consistent with the latte r possibility, Next, it was observed that as carcinoma multiplicity in creased, the discordance rate of ras12 genotypes among multiple carcin omas within the same animal increased in a manner that was in excellen t agreement with the expected discordance rate based on an assumption of no pathogenetic association among carcinomas, Furthermore, a signif icant difference was observed in the occurrence of mutant ras12 carcin omas between the cervical-thoracic and the abdominal-inguinal mammary glands in that three times as many carcinomas were mutant in the forme r as in the latter glands, whereas the occurrence of wild-type carcino mas was approximately the same in both regions, Taken together, the da ta are consistent with (i) carcinomas induced by MNU and detected by p alpation are monoclonal in origin, (ii) independently-initiated cells emerge as distinct mammary carcinomas in the same animal, and (iii) th e anatomical location of the gland may affect the prevalence of mammar y carcinomas that harbor a mutant ras12.