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Gene Signaling Pathways Mediating the Opposite Effects of Prepubertal Low-Fat and High-Fat n-3 Polyunsaturated Fatty Acid Diets on Mammary Cancer Risk

Authors' Affiliations: ¹ Cancer Prevention Fellowship Program, Office of Preventive Oncology, Division of Cancer Prevention, and ² Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ³ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; and ⁴ Virginia Polytechnic Institute and State University, Arlington, Virginia

Requests for reprints: Leena Hilakivi-Clarke, 3970 Reservoir Road, Northwest, Research Building, Room W405, Washington, DC 20057. Phone: 202-687-7237; Fax: 202-687-7505; E-mail: clarkel{at}georgetown.edu.

In rats, prepubertal exposure to low-fat diet containing n-3 polyunsaturated fatty acids (PUFA) reduces mammary cell proliferation, increases apoptosis, and lowers risk of mammary tumors in adulthood, whereas prepubertal high-fat n-3 PUFA exposure has opposite effects. To identify signaling pathways mediating these effects, we performed gene microarray analyses and determined protein levels of genes related to mammary epithelial cell proliferation. Nursing female rats and rat pups were fed low-fat (16% energy from fat) or high-fat (39% energy from fat) n-3 or n-6 PUFA diets between postnatal days 5 and 24. cDNA gene expression microarrays were used to identify global changes in the mammary glands of 50-day-old rats. Differences in gene expression were confirmed by real-time quantitative PCR, and immunohistochemistry was used to assess changes in the peroxisome proliferator–activated receptor and cyclin D1 levels. DNA damage was determined by 8-hydroxy-2'-deoxyguanosine assay. Expressions of the antioxidant genes thioredoxin, heme oxygenase, NADP-dependent isocitrate dehydrogenase, and metallothionein III, as well as peroxisome proliferator–activated receptor protein, were increased in the mammary glands of 50-day-old rats prepubertally fed the low-fat n-3 PUFA diet. Prepubertal exposure to the high-fat n-3 PUFA diet increased DNA damage and cyclin D1 protein and reduced expression of BRCA1 and cardiotrophin-1. Reduction in mammary tumorigenesis among rats prepubertally fed a low-fat n-3 PUFA diet was associated with an up-regulation of antioxidant genes, whereas the increase in mammary tumorigenesis in the high-fat n-3 PUFA fed rats was linked to up-regulation of genes that induce cell proliferation and down-regulation of genes that repair DNA damage and induce apoptosis.

Key Words: 8-hydroxy-2'-deoxyguanosine, 8-OHdG • BRCA1, breast cancer 1 • PCR • polyunsaturated fatty acid, PUFA