Epigenetics of breast cancer: polycyclic aromatic hydrocarbons as risk factors.
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 PAH-metabolites. 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]P-treated cells coincides with disruption of cell cycle kinetics and accumulation of p53. These effects are counteracted by the AhR-antagonist alpha-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.
Jeffy
Brandon D
BD
Cancer Biology Interdisciplinary Program, The University of Arizona, Tucson, Arizona 85721-0038, USA.
Chirnomas
Ryan B
RB
Romagnolo
Donato F
DF
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019398:Genes, BRCA1 / Q000187:drug effects*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D019313:BRCA1 Protein; D001571:Benzoflavones; D002273:Carcinogens; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C011512:alpha-naphthoflavone