Genetic Control of Resistance to Chemically Induced Mammary Adenocarcinogenesis in the Rat

Fifty-day-old female rats of a series of outbred (i.e., SD) and inbred (i.e., NSD, WF, LEW, F344, ACI, and COP) strains were exposed to a single dose of either of two highly effective mammary chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) or 1-methyl-1-nitrosourea (MNU), to determine the characteristic number of mammary adenocarcinomas induced/rat for each strain. Female rats of the inbred NSD, WF, and LEW strains were found to be as highly susceptible to DMBA exposure as the randomly outbred SD strain (i.e., >2 mammary adenocarcinomas/rat develop). Inbred female F344 and ACI rats were found to be much less susceptible to DMBA induced mammary adenocarcinogenesis (i.e., <1.2 mammary adenocarcinomas/rat). In contrast to all the other inbred strains, the female COP rat was unique in that it is essentially completely resistant to all attempts to induce mammary adenocarcinomas by either DMBA or MNU exposure. Genetic breeding analysis demonstrated that the resistance of the mammary epithelium of the female COP rat to DMBA and MNU is due to the mendelian inheritance of a dominant, autosomal genetic allele. The inheritance of a single copy of this resistance allele is able to prevent both the DMBA and MNU induced development of mammary adenocarcinomas in F1 hybrids produced by cross-breeding COP to the highly susceptible NSD animal.