title: Mechanisms mediating the effects of prepubertal (n-3) polyunsaturated fatty acid diet on breast cancer risk in rats.
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.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA. clarkel@georgetown.edu
authors.forename: Leena
authors.initials: L
authors.lastname: Hilakivi-Clarke
authors.forename: Susan E
authors.initials: SE
authors.lastname: Olivo
authors.forename: Ayesha
authors.initials: A
authors.lastname: Shajahan
authors.forename: Galam
authors.initials: G
authors.lastname: Khan
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Alan
authors.initials: A
authors.lastname: Zwart
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cho
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001943:Breast Neoplasms / Q000517:prevention & control; D002273:Carcinogens; D004032:Diet; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats
chemical_list: D002273:Carcinogens; D005231:Fatty Acids, Unsaturated; D015127:9,10-Dimethyl-1,2-benzanthracene