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Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids.

Berquin IM, Min Y, Wu R, Wu J, Perry D, Cline JM, Thomas MJ, Thornburg T, Kulik G, Smith A, Edwards IJ, D'Agostino R, Zhang H, Wu H, Kang JX, Chen YQ

Department of Cancer Biology, Department of Pathology, Department of Biochemistry, Comprehensive Cancer Center, and Department of Biostatistical Science, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. Laboratory of Food Biotechnology, School of Food Science and Technology, Southern Yangtze University, Wuxi, People’s Republic of China. Department of Molecular and Medical Pharmacology, UCLA David Geffen School of Medicine, Los Angeles, California, USA. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Although a causal role of genetic alterations in human cancer is well established, it is still unclear whether dietary fat can modulate cancer risk in a predisposed population. Epidemiological studies suggest that diets rich in omega-3 polyunsaturated fatty acids reduce cancer incidence. To determine the influence of fatty acids on prostate cancer risk in animals with a defined genetic lesion, we used prostate-specific Pten-knockout mice, an immune-competent, orthotopic prostate cancer model, and diets with defined polyunsaturated fatty acid levels. We found that omega-3 fatty acids reduced prostate tumor growth, slowed histopathological progression, and increased survival, whereas omega-6 fatty acids had opposite effects. Introducing an omega-3 desaturase, which converts omega-6 to omega-3 fatty acids, into the Pten-knockout mice reduced tumor growth similarly to the omega-3 diet. Tumors from mice on the omega-3 diet had lower proportions of phosphorylated Bad and higher apoptotic indexes compared with those from mice on omega-6 diet. Knockdown of Bad eliminated omega-3-induced cell death, and introduction of exogenous Bad restored the sensitivity to omega-3 fatty acids. Our data suggest that modulation of prostate cancer development by polyunsaturated fatty acids is mediated in part through Bad-dependent apoptosis. This study highlights the importance of gene-diet interactions in prostate cancer.

Published 3 July 2007 in J Clin Invest, 117(7): 1866-1875.
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