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.