REGULATION OF MEVALONATE SYNTHESIS IN RAT MAMMARY-GLANDS BY DIETARY N-3 AND N-6 POLYUNSATURATED FATTY-ACIDS

It is well established that dietary n-6 polyunsaturated fatty acids (P UFAs) enhance rat mammary tumor development whereas n-3 PUFAs inhibit it, Set the mechanisms are unclear. The objective of this study was to investigate a mechanism by which n-3 and n-6 PUFAs could modulate mam mary carcinogenesis. Female Sprague Damley rats were fed diets contain ing either menhaden (n-3) or safflower oil (n-6) in a 7% fat diet for 1 week. In comparison to the n-6 diet, the n-3 diet significantly redu ced the activity and levels of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA ) reductase in mammary glands, thereby suppressing the formation of me valonate. In addition to being essential for cholesterol biosynthesis, mevalonate is also required for DNA synthesis and may be involved in malignant transformation. Serum cholesterol was lower in the n-3 group than in the n-6 group (1.91 +/- 0.18 versus 2.61 +/- 0.37 mM; P < 0.0 1). Extrahepatic tissues meet most of their cholesterol requirements f rom circulating cholesterol, and the internalized cholesterol down-reg ulates HMG-CoA reductase. Thus, the concomitant decrease in serum chol esterol and mammary gland HMG-CoA reductase levels suggests that chang es in circulating cholesterol levels do not solely determine the activ ity of extrahepatic reductase. We conclude that the mevalonate pathway may be a mechanism through which different types of dietary fat modul ate breast cancer development.