NMU INDUCED MAMMARY CANCER AND OMEGA 3 FATTY ACIDS

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The purpose of this study is to determine the role played by omega-3 fatty acids in mammary carcinogenesis. The N- nitrosomethylurea-(MNU)- induced rat mammary tumor will serve as a model for human breast cancer. The experimental diets are designed such that the ratio of omega-6/omega-3 fatty acids will vary form 7:1 to 2:1 and 0.7:1. (The ratio in the contemporary Western diet is approximately 10:1). The experimental diets will be fed at 23% (wt/wt), which approximates the current U.S. fat intake. High-fat (HF) and low-fat (LF) corn oil (23% and 5%, respectively) will serve as internal controls. If the balance of omega-6/omega-3 fatty acids plays a determining role in mammary tumor development, then tumor incidence should approach that of the LF corn oil group as omega-3 levels increase; if, on the other hand omega-3 fatty acids have effects similar to omega-6 fatty acids, then tumor incidences should remain in the HF corn oil range. The experimental protocols are designed to test the effects of omega-3 fatty acids on (a) the initiation phase, (b) the promotion phase, and (c) both the initiation and promotion phases. In this way, the stage in carcinogenesis at which the optimal chemopreventive effects of omega-3 fatty acids are exerted can be determined. Such information is important, both theoretically and in the design of dietary intervention trials. Evidence suggest that omega-3 fatty acids compete with omega-6 fatty acids for common metabolic pathways. As a result omega-3 fatty acids may replace omega-6 fatty acids in cell membranes, thereby altering the structural and functional integrity of the membrane. Since diet has been shown to alter serum prolactin levels and prolactin receptor status, we propose to test the hypothesis that the tumor-inhibiting effects of omega-3 diets may be exerted via changes in membrane-bound prolactin receptors and/or changes in circulating levels of prolactin, a known tumor promoter. To test this hypothesis, the fatty acid composition of (a) serum neutral and phospholipids and (b) tumor neutral lipids and the four new major subclasses of phospholipids, namely, phosphatidyl choline, phosphatidyl inositol, phosphatidyl serine and phosphatidyl ethanolamine will be determined. In addition, both immunoassayable and bioassayable serum prolactin and tumor prolactin receptor content will be assessed in each treatment group. The ultimate objective of this proposal is the development of an optimal omega-6/omega-3 dietary fatty acid balance for the primary and secondary prevention of breast cancer in high-risk countries, such as the U.S.A.