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Regulation of Mevalonate Synthesis in Rat Mammary Glands by Dietary n-3 and n-6 Polyunsaturated Fatty Acids¹

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Canada M5S 3E2

It is well established that dietary n-6 polyunsaturated fatty acids (PU-FAs) enhance rat mammary tumor development whereas n-3 PUFAs inhibit it, yet the mechanisms are unclear. The objective of this study was to investigate a mechanism by which n-3 and n-6 PUFAs could modulate mammary carcinogenesis. Female Sprague Dawley rats were fed diets containing 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 reduced the activity and levels of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in mammary glands, thereby suppressing the formation of mevalonate. 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 < 0.01). Extrahepatic tissues meet most of their cholesterol requirements from circulating cholesterol, and the internalized cholesterol down-regulates HMG-CoA reductase. Thus, the concomitant decrease in serum cholesterol and mammary gland HMG-CoA reductase levels suggests that changes in circulating cholesterol levels do not solely determine the activity of extrahepatic reductase. We conclude that the mevalonate pathway may be a mechanism through which different types of dietary fat modulate breast cancer development.

¹ This investigation was supported by a grant from the Canadian Breast Cancer Research Initiative. M. C. A. is the recipient of a Natural Sciences and Engineering Research Council of Canada Industrial Research Chair and acknowledges support from the member companies of the Program in Food Safety (University of Toronto). A. E-S. is the recipient of a Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship.

² To whom requests for reprints should be addressed, at Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College Street, Toronto, Canada M5S 3E2. Phone: (416) 978-8195; Fax: (416) 978-5882; E-mail: m.archer@utoronto.ca.

Received 6/ 6/97. Accepted 7/17/97.

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