TIMING OF DIETARY-FAT EXPOSURE AND MAMMARY TUMORIGENESIS - ROLE OF ESTROGEN-RECEPTOR AND PROTEIN-KINASE-C ACTIVITY

The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conf licting data obtained from migrant, case control and animal studies, w hich generally support this association, and cohort studies which ofte n fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during fetal development, lead ing us to hypothesize that dietary fat levels during this period may s ignificantly influence breast cancer risk. Using chemically-induced ma mmary tumors in rats as our experimental model, we have demonstrated t he ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelera te the onset of sexual maturation, and increase breast cancer risk. Th e mammary glands of female rats exposed to a high-fat diet in utero ha ve more of the undifferentiated structures (terminal end buds) and few er of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary g lands contain lower levels of total estrogen receptors and have reduce d total protein kinase C activity. These effects appear to be mediated by an increase in the serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high-fat diet. Furthermor e, the administration of estradiol to pregnant dams produces effects o n mammary gland development, onset of puberty and sensitivity to chemi cal carcinogenesis comparable to those seen in the offspring of rats f ed a high fat diet during pregnancy. Our results, thus, support the hy pothesis based on epidemiological data that high maternal estrogen lev els increase daughters' breast cancer risk. The results also suggest t hat a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.