Resistance to mammary tumorigenesis in Copenhagen rats is associated with the loss of preneoplastic lesions

The resistance of Copenhagen (Cop) rats to mammary tumor development has re cently been linked to three loci, but the genes have yet to be cloned and t he mechanism of resistance is still largely unknown. In order to determine the cellular events associated with resistance, we prepared mammary whole m ounts from Cop and susceptible Wistar Furth (WF) rats 0, 15, 30, 45 and 60 days after treatment with 50 mg/kg N-methyl-N-nitrosourea (MNU), At 15 days , treated rats of both strains had significantly more undifferentiated stru ctures [terminal end buds (TEBs)] and significantly fewer differentiated st ructures [alveolar buds (ABs)] than untreated rats. Treated Cop rats, howev er, had significantly more TEBs and fewer ABs than age-matched, treated WF rats. Histological analysis of preneoplastic lesions tentatively identified from the whole mounts showed that like WF rats, Cop rats developed early p reneoplastic lesions [intraductal proliferations (IDPs)] by 15 days post-MN U treatment. Unlike IDPs from WF rats, however, the IDPs in Cop rats then d ecreased in number until they were absent 60 days post-MNU treatment. Furth ermore, they failed to progress into more advanced lesions such as ductal c arcinomas in situ (DCIS), Finally, we found G-->A activating mutations in c odon 12 of the Ha-ras gene in 60% of IDPs from Cop rats and 75% of IDPs fro m WF rats, Our results show that resistance in Cop rats is not due to a tar get cell population for the carcinogen that is smaller than in susceptible rats or to the failure of the carcinogen to inhibit mammary gland different iation. Furthermore, we have shown that Cop rats develop preneoplastic IDPs that harbor Ha-ras mutations but, unlike IDPs in susceptible strains, they fail to progress and ultimately disappear.