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5-Lipoxygenase and 5-Lipoxygenase-Activating Protein Gene Polymorphisms, Dietary Linoleic Acid, and Risk for Breast Cancer

¹ Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; ² Northern California Cancer Center, Fremont, California; ³ Department of Health Research and Policy, Stanford University School of Medicine; ⁴ Stanford Cancer Center, Stanford, California; and ⁵ Department of Preventive Medicine, University of Southern California, Los Angeles, California

Requests for reprints: Jun Wang, 750 Washington Street, Tufts Medical Center, Box 406, Boston, MA 02111. Phone: 617-638-9437; Fax: 617-636-1542. E-mail: jwang1{at}tuftsmedicalcenter.org

The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenase-activating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, –4900 A>G (rs4076128), and –3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, –1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP –4900 A>G polymorphism and dietary linoleic acid intake (P = 0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age- and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming 17.4 g/d of linoleic acid, ALOX5AP –4900 genotype was not associated with breast cancer risk (age- and race-adjusted odds ratio, 0.9; 95% confidence interval, 0.7-1.2). These results support a role for n-6 polyunsaturated fatty acids in breast carcinogenesis and suggest that epidemiologic studies on dietary fat and breast cancer should take into account genetic predisposition related to n-6 polyunsaturated fatty acid metabolism. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2748–54)