Epigenetics of breast cancer: Polycyclic aromatic hydrocarbons as risk factors

Abstract

In the absence of a causal relationship between the incidence of sporadic breast cancer and occurrence of mutations in breast cancer susceptibility genes, efforts directed to investigating the contribution of environmental xenobiotics in the etiology of sporadic mammary neoplasia are warranted. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants, which have been shown to induce DNA damage and disrupt cell cycle progression. In this report we discuss published data pointing to PAHs as a risk factor in carcinogenesis, and present findings generated in our laboratory suggesting that the mammary tumorigenicity of PAHs may be attributable, at least in part, to disruption of BRCA-1 expression by reactive PAHmetabolites. We report that benzo[a]pyrene (B[a]P), selected as a prototype PAH, disrupts BRCA-1 transcription in estrogen receptor (ER)-positive but not ER-negative breast cancer cells. The reduced potential for BRCA-1 expression in B[a]Ptreated cells coincides with disruption of cell cycle kinetics and accumulation of p53. These effects are counteracted by the AhR-antagonist ␣-naphthoflavone (ANF), and in breast cancer cells expressing mutant p53 or the E6 human papilloma virus protein. We suggest that exposure to PAHs may be a predisposing factor in the etiology of sporadic breast cancer by disrupting the expression of BRCA-1. Environ. Mol. Mutagen. 39:235-244, 2002.

Altered Gene Expression Patterns in MCF-7 Cells Induced by the Urban Dust Particulate Complex Mixture Standard Reference Material 1649a

“…To date, no mutations in the BRCA-1 gene have been identified in sporadic breast cancers, whereas the expression levels of BRCA-1 in breast tumors are lower than those observed in normal mammary tissue (45). Recent work by Jeffy et al (46) suggest that BP, a carcinogenic PAH found in tobacco smoke, environmental pollution, and foods may contribute to breast carcinogenesis through the inhibition of the tumor suppressor gene BRCA-1. Under the experimental conditions used in our study, the global gene expression analysis revealed no alterations in the tumor suppressor gene BRCA-1; however, Jeffy et al (15) in a study of BRCA-1 expression in MCF-7 cells, did see a decrease after 72 hours of BP treatment.…”

Residential environmental exposures and other characteristics associated with detectable PAH-DNA adducts in peripheral mononuclear cells in a population-based sample of adult females

“…PAH bind to DNA forming PAH-DNA adducts, initiating mutagenesis and carcinogenesis (Lijinsky, 1991;Jeffy et al, 2002). Interindividual differences in DNA adduct formation of persons who are exposed to the same external levels suggest that differences in absorption, activation and detoxification mechanisms, DNA repair, cell turnover, cellcycle control, as well as lifestyle or diet can modify individual response to exposure (Harris et al, 1982;Santella, 1999;Wiencke, 2002).…”

Polycyclic Aromatic Hydrocarbon–DNA Adducts and Breast Cancer: A Pooled Analysis

“…Covariates we considered as potential effect modifiers included menopausal status, season of the blood draw, length of residence in the interview home, age at diagnosis, active cigarette smoking, a combined measure of active cigarette smoking and exposure to passive smoking (from the parent or spouse) in the home, alcohol intake, and intake of grilled or smoked foods (as assessed in the main questionnaire). 8 An additional covariate we considered as a potential effect modifier was a measure of total dietary benzo[a]pyrene (BaP), which is one of the major components of PAH 20 and an established carcinogen. 5 The measure used in this analysis was a modification of a PAH food index developed recently by Kazerouni et al 21 that uses data collected as part of the diet history.…”