Dietary fats are known to profoundly influence a broad array of physiological functions. Both level of fat intake and specific types of dietary lipid are implicated in health issues including longevity of life, obesity, metabolic disorders and cancer risk. In particular, degree of saturation of dietary fatty acids is an important factor in breast cancer risk and cardiovascular disease. Despite plentiful epidemiological and clinical correlates, the physiological mechanisms underlying the effects of dietary fats are poorly understood. The broad objectives of this proposal are: 1) to establish a ruminant animal model for studyingthe effects of dietary polyunsaturated and saturated fatty acids on mammary development, and 2) to identify key regulatory mechanism that mediate the effects of dietary lipids on mammary development. The long-term goal of this initial approach is to provide a focal point for future studies on fundamental mechanisms that control normal mammary growth and may predispose to breast cancer susceptibility. The proposed studies will test the hypotheses that effects of dietary fat on mammary development are mediated primarily by modulating: 1) endocrine function (systemic effect), 2) sensitivity of mammary epithelia to mammogenic signals (local effect), or 3) local-acting factors elaborated by the mammary fat pad (paracrine effect). Female dairy cattle will be fed diets high in either saturated or polyunsaturated fatty acids from 3 to 9 months of age. Cattles were chosen as subjectsbased on: 1) their characteristic low levels of polyunsaturated fattyacids in body fat and the ability to markedly increase levels by dietary manipulation; 2) the demonstrated sensitivity of ruminant mammary development to dietary perturbation at this age; and 3) access to large amounts of tissues for analyses. Endocrine function will be assessed using bovine mammary epithelial cells to bioassay mammogenic capacity of sera and by measuring concentrations of mammogenic hormones (prolactin, growth hormone, insulin, and IGF-1) in sera. Hormone receptors will be quantified in liver and mammary tissue. Sensitivity of mammary epithelia will be evaluated by measuring responseto stimulatory hormones in vitro. In addition, mammary cells will be co-cultured with explants of mammary fat pad to determine the ability of fat pad to promote cell proliferation in vitro.
