Epidemiologic studies among populations that consume moderate to high amount of soy have shown that soy isoflavones may reduce breast cancer risk, and the chemopreventive effects are postulated to be related to the anti-estrogenic properties of soy isoflavones. Recently, experimental studies have revealed that dietary isoflavones may also down-regulate the expression of the MDM2 oncogene, and the inhibition of the expression of the MDM2 oncoprotein has in turn been associated with antitumor activities in breast cancer models. Furthermore, a polymorphism in the promoter region of MDM2 SNP309 (T>G change at nucleotide 309 in the first intron; rs2279744) leads to increased expression of the oncogene and has been associated with earlier onset of breast cancer. We have previously shown that postmenopausal women with a higher than median intake of soy have a reduced risk of breast cancer compared with those with a lower intake. If down-regulation of the MDM2 oncogene is one of the mechanistic pathways for the chemopreventive effects of soy isoflavones in breast cancer, we postulate that the protective effect of soy isoflavones on breast cancer will be stronger in those possessing the high-activity MDM2 genotype. To confirm this hypothesis, we conducted a nested case-control study among 281 incident, postmenopausal breast cancer cases and 462 postmenopausal control subjects within the Singapore Chinese Health Study Cohort. Overall, there was no significant association between MDM2 gene polymorphism and breast cancer risk. Postmenopausal women who had a higher than median intake of soy had a reduced risk of breast cancer [odds ratio (OR), 0.76; 95% confidence interval (CI), 0.56-1.03]. This inverse association was principally noted among women homozygous for the high activity MDM2 allele (GG genotype). There was a statistically significant, roughly 50% reduction in breast cancer risk between above versus below median level of soy consumption in this subgroup of women (OR, 0.52; 95% confidence interval, 0.28-0.98). On the other hand, a much weaker, and statistically nonsignificant association was noted among women possessing the lower-activity MDM2 genotypes (OR, 0.86, 95% CI, 0.59-1.24). Our findings suggest that the ability of soy isoflavones to down-regulate the MDM2 oncoprotein may be one etiologic mechanism through which the intake of soy is associated with breast cancer protection.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 912.