Mechanisms mediating the effects of prepubertal (n-3) polyunsaturated fatty acid diet on breast cancer risk in rats

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.