ras may mediate mammary cancer promotion by high fat.

High fat consumption has been implicated as a risk factor for breast cancer. Experimental mammary carcinogenesis studies have demonstrated that the effect of high fat consumption is mainly exerted on the postinitiation stage of the disease process. We report data that have recalled in the formulation of a new hypothesis about the effect of dietary fat on mammary carcinogenesis, namely, that it promotes the development of a subpopulation of cells lacking a specific pathogenetic characteristic. In comparison with animals fed a low-fat diet, female Sprague-Dawley rats fed high-fat diets during the promotional stage developed significantly more (number and proportion) 1-methyl-1-nitrosourea-induced mammary adenocarcinomas that did not contain a codon 12 GGA-->GAA mutation in the c-Ha-ras protooncogene. The effect was independent of the types of fat fed, i.e., corn oil vs. fish oil. A model is presented to account for the preferential promotional effect of high fat consumption on 1-methyl-1-nitrosourea-initiated mammary epithelial cells. The hypothesis that the level of dietary fat consumed affects the proportion of mammary carcinomas that occur with a particular pathogenetic characteristic, in this case, the presence or absence of a Ha-ras point mutation, has important implications on the direction of future investigations concerning fat and cancer risk.