Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

Goth-Goldstein, Regine ; Russell, Marion L. ; Muller, A.P. ; Caleffi, M. ; Eschiletti, J. ; Graudenz, M. ; Sohn, Michael D.

关键词: 54;    ADDUCTS;    AROMATICS;    CYTOCHROMES;    DIET;    DNA;    DNA ADDUCTS;    DRINKING WATER;    ENZYMES;    ESTROGENS;    ETIOLOGY;    GENES;    GENOTYPE;    MAMMARY GLANDS;    METABOLISM;    MUTATIONS;    NEOPLASMS;    ORGANIC MATTER;    POLYCYCLIC AROMATIC HYDROCARBONS;    SURGERY;    TRANSFORMATIONS;   

DOI  :  10.2172/983194
RP-ID  :  LBNL-3324E
PID  :  OSTI ID: 983194
Others  :  TRN: US201014%%587

美国|英语

来源: SciTech Connect

【 摘 要 】

This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.