Influence of Estrogenic Metabolic Pathway Genes Polymorphisms on Postmenopausal Breast Cancer Risk

Abstract

Estrogen metabolism plays an important role in tumor initiation and development. Lifetime exposure to high estrogens levels and deregulation of enzymes involved in estrogen biosynthetic and metabolic pathway are considered risk factors for breast cancer. The present study aimed to evaluate the impact of mutations acquisition during the lifetime in low penetrance genes that codify enzymes responsible for estrogen detoxification. Genotype analysis of GSTM1 and GSTT1 null polymorphisms, CYP1B1 Val432Leu and MTHFR C677T polymorphisms was performed in 157 samples of women with hormone-dependent breast cancer and correlated with the age at diagnosis. The majority of patients with GSTT1 null genotype and with both GSTM1 and GSTT1 null genotypes were 50 years old or more at the diagnosis (p-value = 0.021 and 0.018, respectively). Older women with GSTM1 null genotype were also carriers of the CYP1B1Val allele (p-value = 0.012). As well, GSTT1 null and CYP1B1Val genotypes were correlated with diagnosis at later ages (p-value = 0.022). Similar results were found associating MTHFR C677T and GSTT1 null polymorphism (p-value = 0.034). Our results suggest that estrogen metabolic pathway polymorphisms constitute a factor to be considered simultaneously with models for breast cancer risk assessment.

Keywords: CYP1B1; GSTM1; GSTT1; MTHFR; breast cancer.

Figure 1

Schematic representation of the metabolic pathway of Oestradiol. CYP1B1, a Phase I enzyme, codified by the CYP1B1 gene, leads to 4-OH-E2 production. The Phase II enzymes, COMT, codified by the COMT gene, and GSTM1/GSTT1, codified by GSTM1 and GSTT1 genes, respectively, inactivate the estrogen catechol, semiquinone and quinone, diminishing DNA adducts formation. MTHFR, an enzyme of the folate metabolism, catalyzes 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which allows the remethylation of homocysteine to methionine, a precursor of S-adenosylmethionine (SAM). SAM is the methyl donor for COMT catalyzed reactions, allowing the inactivation of catechol estrogens.