Dietary and genetic factors in the etiology of prostate cancer

Abstract: The etiology of prostate cancer is poorly understood. However, genetic factors may be more important than for many other malignancies. In addition, several studies suggest that dietary factors axe of etiologic importance. In particular, dietary intake of phytoestrogens or marine fatty adds from fish may protect against prostate cancer development. Because phytoestrogens bind tightly to the estrogen receptor-beta that is involved in prostate cancer progression, we investigated whether there is a synergistic effect between phytoestrogen intake and estrogen receptor-beta (ERbeta) gene polymorphisms in prostate cancer development. Furthermore, we investigated the interaction between intake of fatty fish and polymorphisms in the cyclooxygenase (COX)-2 gene, a key enzyme in fatty add metabolism and inflammation. Finally, we examined whether the association of alcohol consumption with prostate cancer risk varies between localized and advanced cases, or between sporadic and familial cases. We conducted a large population-based case-control study in Sweden (CAPS); in this study, we assessed dietary intake of phytoestrogens, fish consumption and alcohol drinking among 1499 cases and 1130 controls. Scrum enterolactone levels were analyzed for 209 cases and 214 controls, chosen randomly. We identified four single nucleotide polymorphisms (SNPs) in the ERbeta gene and five in the COX-2 gene, and genotyped these SNPs in 1314 (ERbeta) or 1378 (COX2) cases and 782 controls, respectively. Unconditional logistic regression was performed to estimate multivariate odds ratios and 95% confidence intervals. Stratified analyses, as well as both multiplicative and additive models, were used to evaluate interactions between dietary intake and SNPs on prostate cancer risk. We found that high intake of food items rich in phytoestrogens was strongly associated with a decreased relative risk of prostate cancer, and intermediate serum levels of enterolactone were associated with a decreased relative risk. Furthermore, we found that the overall decreased risk of prostate cancer for men with a high intake of phytoestrogens was strongly modified by a promoter SNP in the ERbeta gene (-13950 T/C). Carriers of the variant allele had an almost 60% lower risk of prostate cancer, compared to men with low phytoestrogen intake, whereas no such association was found among men with the common genotype. Frequent consumption of fatty fish or marine fatty adds was strongly associated with a decreased relative risk of prostate cancer. The inverse association between salmon-type fish and prostate cancer was modified by a nucleotide sequence variant in the COX-2 gene (+6365 T/C). Prostate cancer cases were more likely than controls to be current or former, rather than never, drinkers. However, there was no association between recent alcohol consumption and risk of overall prostate cancer, nor advanced, sporadic, or familial prostate cancer. There was a marginal positive association between intake of any alcohol type and risk of localized disease. In summary, our study provides strong evidence that high intake of phytoestrogens substantially reduces prostate cancer risk among men with specific polymorphic variation in the promoter region of the ERbeta gene. In addition, frequent consumption of fatty fish and marine fatty acids strongly reduces the risk of prostate cancer, and this association appears to be modified by genetic variation in the COX-2 gene. Furthermore, we found no association between recent alcohol consumption and risk of overall prostate cancer, although we observed a marginal positive association with localized disease.