Inheritance of a genetic factor from the Copenhagen rat and the suppression of chemically induced mammary adenocarcinogenesis.

Female rats of ten different inbred strains were tested for their susceptibility to 7, 12-dimethylbenz[a]anthracene (DMBA)-induced mammary adenocarcinogenesis. Five of these strains (OM, NSD, WF, LEWIS, BUFF) were demonstrated to be highly susceptible to DMBA exposure developing greater than 2 continuously growing, macroscopically detectable mammary adenocarcinomas/rat following gastric intubation with DMBA. In contrast, the COP female rat is completely resistant. Cross-breeding COP to any of the highly susceptible strains produced F1 hybrids which are resistant to DMBA-induced mammary adenocarcinogenesis. Cross-breeding the same highly susceptible strains to the Fischer strain (i.e., a strain only intermediately susceptible to DMBA) produced F1 hybrids which were just as highly inducible as their highly susceptible non-Fischer parental strain. The resistance of the F1 hybrids produced by cross-breeding these highly susceptible strains to the COP strain therefore is not due to a recessive lack of susceptibility but to an active process of suppression of the high susceptibility of these F1 hybrids to DMBA-induced mammary adenocarcinogenesis. To determine if the site of action of the COP gene responsible for this suppression is in the mammary gland itself or at the host systemic level, a series of factors (i.e., host growth rate, mammary gland growth rate, systemic hormone level during the estrus cycle, serum and tissue levels of DMBA and its metabolites) were compared between female rats of the highly susceptible NSD versus the resistant COP strain. These results suggested that host systemic factors are not involved. To test this directly, donor mammary glands from the highly susceptible NSD and the resistant COP strains were transplanted into F1 hybrids produced by cross-breeding these two strains. The resultant donor glands were then directly exposed to DMBA, the animals were followed, and the incidence of mammary adenocarcinomas was determined. Seventy % of the NSD donor glands developed continuously growing cancers while only 10% of COP donor glands did the same. These results are clearly incompatible with host systemic factors being the major determinant in the resistance of NSD X COP F1 hybrids to DMBA-induced mammary adenocarcinogenesis. Instead, these results directly demonstrate that it is the genetic makeup of the donor mammary gland itself which determines its response to DMBA exposure.