Interindividual Differences in Metabolism of Carcinogens as a Risk Factor for Breast Cancer

Abstract

Abstract : The proposed study seeks to address the interaction of environmental and genetic factors in the etiology of breast cancer. The cytochrome P450 isozymes CYPlAl and CYP1B1 metabolize environmental and endogenously formed carcinogens in the breast. We are testing the hypothesis that individuals with higher levels of CYP1B1 are at a higher risk for breast cancer because they produce higher amounts of ultimate carcinogen. Genetic polymorphism and expression level of CYP1A1 and CYP1B1 are being determined in a collection of nontumor breast tissue samples from reduction mammoplasties and from mastectomy patients. Frequency of genetic variants and expression is compared in specimens from cancer patients and health controls to establish if breast cancer patients have an increased level of the enzyme. During the last year CYP1B1 and in parallel CYP1A1 expression was determined in an additional 29 specimens using a semiquantitative RT-PCR. All available specimens were analyzed for known genetic polymorphisms in the CYP1A1 and CYP1B1 genes. The difference in variant frequencies between cases and controls was not significant. CYP1B1 transcript levels ranged from 1.5 to 133. CYP1A1 level had an even larger interindividual range. In most specimen CYP1B1 expression was 2-6 fold that of CYP1A1. CYP1B1 expression was significantly higher in the breast cancer group than in the healthy control group.