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

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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.

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Jeffy, B. D., Schultz, E. U., Selmin, O., Gudas, J. M., Bowden, G. T., & Romagnolo, D. (1999). Inhibition of BRCA-1 expression by benzo[a]pyrene and its diol epoxide. Molecular Carcinogenesis, 26(2), 100–118. https://doi.org/10.1002/(SICI)1098-2744(199910)26:2<100::AID-MC5>3.0.CO;2-1

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