Effect of dietary fat or tamoxifen on the expansion of cells harboring Ha-ras oncogenes in mammary glands from methylnitrosourea-treated rats

Diets containing high levels of fat enhance the formation of methylnitrosourea (MNU)-induced mammary gland adenocarcinomas in rats, while administration of the antiestrogen tamoxifen decreases the incidence of these tumors. It is not known, however, at what stage during tumor development the fat or tamoxifen exert their effects. Here we have used a PCR/liquid hybridization and gel retardation assay to determine the effects of dietary fat and tamoxifen on the growth rate of cells harboring an Ha-ras oncogene in the mammary glands of rats at various times following MNU administration. Glands from animals on a high-fat diet had significantly higher mutant cell fractions than those on a low-fat diet at both 30 and 75 days following MNU treatment. In contrast, there was no difference between the mutant cell fractions of tamoxifen-treated animals and controls at either 30 or 70 days. These results suggest that dietary fat promotes tumor formation early in carcinogenesis by stimulating the growth of cells harboring Ha-ras mutations, while tamoxifen delays the appearance of tumors either by acting as a tumoristatic or tumoricidal agent, or by acting to eliminate or retard the growth of preneoplastic cells just prior to the emergence of tumors.