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 methylnit rosourea (MNU)-induced mammary gland adenocarcinomas in rats, while ad ministration of the antiestrogen tamoxifen decreases the incidence of these tumors. It is not known, however, at what stage during tumor dev elopment the fat or tamoxifen exert their effects. Here we have used a PCR/liquid hybridization and gel retardation assay to determine the e ffects of dietary fat and tamoxifen on the growth rate of cells harbor ing an Ha-ras oncogene in the mammary glands of rats at various times following MNU administration. Glands from animals on a high-fat diet h ad significantly higher mutant cell fractions than those on a low-fat diet at both 30 and 75 days following MNU treatment. In contrast, ther e was no difference between the mutant cell fractions of tamoxifen-tre ated animals and controls at either 30 or 70 days. These results sugge st that dietary fat promotes tumor formation early in carcinogenesis b y stimulating the growth of cells harboring Ha-ras mutations, while ta moxifen delays the appearance of tumors either by acting as a tumorist atic or tumoricidal agent, or by acting to eliminate or retard the gro wth of preneoplastic cells just prior to the emergence of tumors.