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Supplement: International Conference on Diet, Nutrition, and Cancer

Mechanisms Mediating the Effects of Prepubertal (n-3) Polyunsaturated Fatty Acid Diet on Breast Cancer Risk in Rats^1,2

Department of Oncology, Georgetown University Medical Center, Washington, DC 20057

³To whom correspondence should be addressed. E-mail: clarkel{at}georgetown.edu.

ABSTRACT

Dietary exposures during childhood may influence later breast cancer risk. We tested in an animal model the hypothesis that prepubertal intake of (n-3) PUFAs, present mainly in fish, reduces susceptibility to breast cancer. Between postnatal days 5 to 25, rat pups were fed (n-3) PUFA–containing diets at a 2:1 ratio of (n-6):(n-3) PUFAs (typical of prehistoric societies) or a control (n-6) PUFA diet at a 17:1 ratio of (n-6):(n-3) PUFAs (comparable with current Western societies). These fatty acids were given in a low- or high-fat context (16 or 39% energy from fat). The low–(n-3) PUFA diet reduced while the high–(n-3) PUFA diet increased carcinogen-induced mammary tumorigenesis. The low–(n-3) PUFA diet reduced mammary cell proliferation and increased apoptosis, particularly in the terminal end buds (the mammary source of malignant breast tumors). The high–(n-3) PUFA diet had opposite effects on these 2 key biomarkers and increased phospho-Akt levels, a survival factor. Microarray analyses identified genes that were permanently upregulated in the low–(n-3) PUFA–exposed glands and function in oxidative damage repair. Serum levels of 8-hydroxy-2'deoxyguanosine, a marker of DNA damage, were significantly reduced in these low–(n-3) PUFA–fed rats, and increased in the high–(n-3) PUFA–exposed group. The latter group exhibited reduced expression of BRCA1, a DNA repair gene. Our results indicate that the opposing susceptibilities to mammary tumorigenesis between the low- versus high-fat (n-3) PUFA–exposed groups were associated with altered DNA damage repair and gene expression linked to proliferation, survival, and differentiation.

KEY WORDS: • (n-3) polyunsaturated fatty acids • prepubertal diet • mammary tumorigenesis