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

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]pyren e (B[a]P) inhibited in a time- and dose-dependent fashion cell proliferatio n 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 B RCA-1 expression was prevented by the aromatic hydrocarbon receptor (AhR) a ntagonist alpha-naphthoflavone, suggesting participation of the AhR pathway . BRCA-1 exon 1a transcripts were downregulated by B[a]P faster than exon 1 b mRNA was. Long-term exposure to B[a]P (40 nM for 15 mo) lowered BRCA-1 mR NA 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. Th e mechanisms of BRCA-1 repression by B[a]P were further investigated by exa mining the effects of the halogenated aryl hydrocarbon 2,3,7,8-tetrachlorod ibenzo-p-dioxin (TCDD) and the B[a]P metabolite 7r,8t-dihydroxy-9t, 10t-epo xy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). While TCDD did not influence b asal BRCA-1 mRNA and protein levels at any of the doses (from 10 nM to 1 mu M) tested in this study, treatment with 50 nM BPDE drastically reduced BRC A-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[a]P or TCDD and exp ressed constant levels of BRCA-1 mRNA and protein. We conclude that B[a]P m ay be a risk factor in the etiology of sporadic breast cancer. (C) 1999 Wil ey-Liss, Inc.