title: Inhibition of BRCA-1 expression by benzo[a]pyrene and its diol epoxide.
abstract: The objective of this study was to investigate whether polycyclic aromatic hydrocarbons (PAHs) contribute to the etiology of sporadic breast cancer by altering the expression of BRCA-1. Acute exposure to the PAH benzo[a]pyrene (B[a]P) inhibited in a time- and dose-dependent fashion cell proliferation and levels of BRCA-1 mRNA and protein in estrogen receptor (ER)-positive breast MCF-7 and ovarian BG-1 cancer cells. Moreover, the acute exposure to B[a]P abrogated estrogen induction of BRCA-1 in MCF-7 cells. The loss of BRCA-1 expression was prevented by the aromatic hydrocarbon receptor (AhR) antagonist alpha-naphthoflavone, suggesting participation of the AhR pathway. BRCA-1 exon 1a transcripts were downregulated by B[a]P faster than exon 1b mRNA was. Long-term exposure to B[a]P (40 nM for 15 mo) lowered BRCA-1 mRNA levels in subclones of MCF-7 and BG-1 cells, whereas expression of BRCA-1 in these clones was reverted to normal levels by washing out of B[a]P. The mechanisms of BRCA-1 repression by B[a]P were further investigated by examining the effects of the halogenated aryl hydrocarbon 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) and the B[a]P metabolite 7r, 8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). While TCDD did not influence basal BRCA-1 mRNA and protein levels at any of the doses (from 10 nM to 1 microM) tested in this study, treatment with 50 nM BPDE drastically reduced BRCA-1 mRNA levels, indicating that metabolism of B[a]P to BPDE may contribute to downregulation of BRCA-1. Conversely, ER-negative breast MDA-MB-231 and HBL-100 cancer cells were refractory to treatment with B[a]P or TCDD and expressed constant levels of BRCA-1 mRNA and protein. We conclude that B[a]P may be a risk factor in the etiology of sporadic breast cancer.
authors.affiliation: Laboratory of Mammary Gland Biology, Department of Animal Sciences, The University of Arizona, Tucson, Arizona 85721-0038, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Jeffy
authors.forename: E U
authors.initials: EU
authors.lastname: Schultz
authors.forename: O
authors.initials: O
authors.lastname: Selmin
authors.forename: J M
authors.initials: JM
authors.lastname: Gudas
authors.forename: G T
authors.initials: GT
authors.lastname: Bowden
authors.forename: D
authors.initials: D
authors.lastname: Romagnolo
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019398:Genes, BRCA1 / Q000187:drug effects*; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide