Role of CYP1B1 in PAH-DNA Adduct Formation and Breast Cancer Risk

Interindividual variation in carcinogen metabolism is an important determinant of susceptibility to various cancers. In breast tissue, the major enzyme involved in metabolizing polycyclic aromatic hydrocarbons (PAHs) to reactive intermediates appears to be the cytochrome P45O enzyme CYPlB1. High CYPlB1 enzyme levels may result in increased formation of PAH-DNA adducts in breast tissue and lead to subsequent development of breast cancer. Gene expression analysis captures an important convergence of multiple genetic and environmental factors on metabolic enzyme levels. This study tests hypotheses pertaining to underlying molecular mechanisms of the relationship between PAH exposure and breast cancer risk: (1) Increased CYP1B1 gene expression is associated with increased risk of invasive breast cancer; (2) Increased PAH-DNA adduct formation is associated with increased risk of invasive breast cancer; (3) Increased CYP1B1 gene expression is associated with increased PAH-DNA adduct formation in breast cells; and (4) The positive association between CYP1B1 gene expression and increased risk of invasive breast cancer is not due to genotype variation. Given that certain environmental exposures, such as PAHs, appear to be important breast cancer risk factors, establishing biologic pathways through which these agents act will provide new insights for disease prevention.