Inhibition of BRCA-1 expression by benzo[a]pyrene and its diol epoxide

✍ Scribed by Brandon D. Jeffy; Elizabeth U. Schultz; Ornella Selmin; Jean M. Gudas; G. Tim Bowden; Donato Romagnolo

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 364 KB
• Volume: 26
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/(sici)1098-2744(199910)26:2<100::aid-mc5>3.0.co;2-1

✦ Synopsis

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 a-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-pdioxin (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 mM) 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.