Sensitivity to benzo(a)pyrene diol-epoxide associated with risk of breast cancer in young women and modulation by glutathione S-transferase polymorphisms: A case-control study

Mounting epidemiological evidence suggests that smoking may play a role in the etiology of breast cancer. Because smoking-related DNA adducts are dete ctable in both normal and malignant breast tissues, we hypothesized that br east cancer patients may be sensitive to tobacco-induced carcinogenesis, an d this sensitivity could be modulated by variants of metabolic genes. To te st this hypothesis, we evaluated benzo(a)pyrene diol-epoxide (BPDE)-induced mutagen sensitivity and polymorphisms of GSTM1 and GSTT1 in a pilot case-c ontrol study of breast cancer. Short-term cell cultures were established fr om blood samples of 100 female breast cancer patients and 105 healthy contr ols. After 5 h of in vitro exposure to 4 muM of BPDE, we harvested the lymp hocytes for cytogenetic evaluation and recorded and compared the frequency of BPDE-induced chromatid breaks between cases and controls. We used a mult iplex PCR-based assay to simultaneously detect polymorphisms of GSTM1 and G STT1 from genomic DNA. We performed univariate and multivariate logistic re gression analyses and calculated odds ratios (OR) and 95% confidence interv als (CIs). Cases had a significantly higher frequency of chromatid breaks t han did controls (P < 0.0001). The level of chromatid breaks greater than t he median value of controls was associated with a >3-fold increased risk of breast cancer [adjusted odds ratio (ORadj) = 3.11; 95% CI = 1.72-5.64]. Th e risk was more pronounced in those who were < 45 years (ORadj = 4.79; 95% CI = 1.87-12.3), ever-smokers (ORadj = 5.55; 95% CI = 1.85-16.6), alcohol d rinkers (ORadj = 4.64; 95% CI = 1.70-12.7), and those who had the GSTT1 nul l variant (ORadj = 8.01; 95% CI = 1.16-55.3). These data suggest that sensi tivity to BPDE-induced chromosomal aberrations may contribute to the risk o f developing breast cancer, and such sensitivity may be modulated by both g enetic and environmental factors. Larger studies are needed to confirm our findings.