Microsomal Epoxide Hydrolase Variants Are Not Associated with Risk of Breast Cancer

Although it has been difficult to establish an epidemiological link between smoking and increased risk for breast cancer, in vitro and in vivo studies have shown that substances present in cigarette smoke could act as breast tissue carcinogens. Polycyclic aromatic hydrocarbons, for instance, cause mammary tumors in rodents, have been shown to be activated by human mammary cells, and can form DNA adducts (1, 2, 3).

Carcinogens found in tobacco smoke are metabolized via enzymatic mechanisms involving both activation and detoxification. mEH² is a detoxifying enzyme that metabolizes xenobiotic epoxides, including derivatives of polycyclic aromatic hydrocarbons found in cigarette smoke. Genetic polymorphisms within the coding region of the mEPHX gene are known to alter the activity of the enzyme (4). A polymorphism in exon 3 leads to substitution of tyrosine residue 113 to histidine and is associated with reduced enzyme activity. By contrast, a polymorphism in exon 4 leads to substitution of histidine residue 139 to arginine and is associated with enhanced activity. Differences in mEH total activity are more likely to result from variation in protein stability rather than from changes in catalytic activity (5).

Polymorphic variation of mEH could modify the risk of breast cancer in women who smoke, because it appears to affect the ability to detoxify tobacco carcinogens. In this study, we examined the association between mEH polymorphisms and breast cancer risk in the presence of cigarette smoking in pre- and postmenopausal women.

Analyses are based on a subset of women who participated in a case-control study of breast cancer in western New York. The design of that study and the description of the study population have been published elsewhere (6). DNA was available for 267 women with incident, primary, histologically confirmed breast cancer and 293 controls. The mEPHX genotypes were determined by PCR-RFLP assay, as described by Hassett et al. (4).

ORs and 95% CIs were calculated using unconditional logistic regression. ORs were adjusted for age, education, age at menarche, age at first pregnancy, body mass index, family history of breast cancer, and age at menopause for postmenopausal women.

In this study, we evaluated the association between mEH3 or mEH4 genotypes and breast cancer risk. As shown in Table 1, there were no overall relationships between either mEH genotype and breast cancer risk. Stratification of subjects by menopausal status resulted in no significant differences in risk for individuals with polymorphisms at either exon 3 or exon 4, compared with individuals without variant alleles, although there was a slight increase in risk for premenopausal women with the polymorphism in exon 3; the CI included one (OR, 1.5; CI, 0.9–2.6). Furthermore, no association was found between breast cancer and mEH genotypes when cases and controls were stratified by both menopausal and smoking status (ever and never smokers).

The limitations of this study are those of other case-control studies. Overall, the present study had adequate statistical power to detect an OR of 1.8 for the mEH genotypes. However, the study had less power for the analysis of women by smoking and menopausal status. Furthermore, we were limited to a very crude assessment of smoking history that may have limited our ability to detect associations. In addition, the study population was geographically restricted to western New York and composed of Caucasian women, which may limit the generalizability.

In conclusion, this study suggests that there is no significant association between mEH polymorphisms and breast cancer risk overall or for groups defined by menopausal or smoking status. These results need to be further corroborated by other studies because this is the first study reporting on the association of mEH polymorphisms and breast cancer.