Authors
Zhang, Y.; Piece Wise, J.; Holford, T.; Zie, H.; Boyle, P.; Hoar Zahm, S.; Rusiecki, J.; Zou, K.; Zhang, B.; Zhu, Y.; Owens, P.; and Zheng, T.

Title:
Serum Polychlorinated Biphenyls, Cytochrome P-450 1A1 Polymorphisms, and Risk of Breast Cancer in Connecticut Women.

Journal:
American Journal of Epidemiology. 160 (12): 1177-1183. 2004

Summary:
Polychlorinated biphenyls (PCBs) are strong inducers of genes involved in steroid and xenobiotic metabolism, such as human cytochrome P450 1A1 (CYP1A1). CYP1A1 is involved in the metabolism of environmental carcinogens to highly reactive metabolites which have the potential to damage DNA and ultimately lead to carcinogenesis. CYP1A1 is a polymorphic gene with at least seven different variant genotypes. Recent epidemiological and experimental evidence suggests that genetic polymorphisms in CYP1A1 may affect the relation between environmental exposure to PCBs and breast cancer risk.

Zhang et al. conducted a case-control study among women in Connecticut to assess whether women with higher levels of PCBs and specific CYP1A1 genotypes were at increased risk of breast cancer. A total of 475 histologically confirmed incident breast cancer were identified from hospital records, and 502 controls were randomly selected from computerized files of women who had undergone breast surgery and were histologically confirmed to be without breast cancer. A standardized, structured questionnaire was used to obtain information on possible confounding factors such as; reproductive and lactation history, occupation, diet, family history of cancer and demographic factors. Blood samples were collected to determine PCB levels and blood clots were obtained for CYP1A1 genotyping. Three different CYP1A1 polymorphisms (CYP1A1 m1, m2, and m4) were determined and were further categorized as either wildtype (homozygous wild type allele) or variant (heterozygous allele or homozygous variant allele). Serum levels of PCBs were categorized as high or low. Logistic regression was used to quantify the overall association between CYP1A1 genotype, serum PCB levels and the risk of breast cancer.

Women with at least one CYP1A1 m2 variant allele had a two fold increased risk of breast cancer (Odds Ratio (OR) = 2.1, 95% Confidence Interval (CI): 1.1-3.9), and the risk became greater among post-menopausal women (OR=2.4, 95% CI: 1.1-5.0). No increased risk of breast cancer was found for women who carried the m1 or m4 variant genotypes; however a significantly increased risk of breast cancer was detected for women who carried the CYP1A1 m2 variant genotype and had high serum PCB levels in comparison with women with low serum PCB levels who carried the CYP1A1 m2 wildtype. (OR=3.6, 95% CI= 1.5-8.2). This risk was higher among postmenopausal women (OR= 4.3, 95% CI: 1.6-12.0). A borderline significant increase in risk was found for women who carried the m1 variant genotype and had high PCB levels as compared to women who had the wildtype genotype and low PCB levels. There did not appear to be an increased risk of breast cancer with different serum levels of PCBs among women who carried m4 genotypes.

The results of this study indicate that effect modification may be occurring between PCB levels, CYP1A1 genotype and the risk of developing breast cancer. CYP1A1 encodes an enzyme aryl hydrocarbon hydroxylase (AHH), which catalyzes the conversion of aromatic hydrocarbons to potentially mutagenic and carcinogenic epoxides. As PCBs are potent inducers of CYP1A1, PCB-mediated enhanced CYP1A1 activity may play an important role in breast cancer development. Significantly increased risk of breast cancer was found only for the CYP1A1 m2 genotype. Previous experimental studies have shown that this specific genotype is more readily inducible than other CYP1A1 genotypes. Therefore there is a biologically plausible explanation for the results of this study. The greatest extent of CYP1A1 activity results in the highest carcinogen bio-activation, leading to the greatest potential risk of cancer.

In interpreting the results of this study several potential limitations should be considered. Because this was a case-control study, biological samples were collected after disease onset. The current levels of PCBs may not accurately reflect the subjects' PCB exposure during the biologically relevant windows of exposure prior to disease development. Another potential limitation is that the low prevalence of the variant genotype restricted the statistical power of the study to stratify the data by major potential confounders.

In summary, the results of this study support the findings from recent epidemiological investigations suggesting potential effect modification between PCB exposure, the CYP1A1 m2 polymorphism, and breast cancer risk. Larger population-based studies are needed to further investigate the extent at which the interaction between CYP1A1 m2 and PCBs is modified by other variables.