Disruption of Cell Cycle Kinetics by Benzo[a]pyrene: Inverse Expression Patterns of BRCA-1 and p53 in MCF-7 Cells Arrested in S and G2

• Main Authors: Brandon D. Jeffy, Eddy J. Chen, Jean M. Gudas, Donato F. Romagnolo
• Format: Article
• Language: English
• Published: Elsevier 2000-09-01
• Series: Neoplasia: An International Journal for Oncology Research
• Subjects: benzo[a]pyrene; BPDE; BRCA-1; p53; cell cycle kinetics; sporadic breast cancer
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558600800160
• ISSN: 1476-5586; 1522-8002

The effects of a ligand of the aromatic hydrocarbon receptor (AhR), benzo[a]pyrene(B[a]P), and its metabolite, BPDE (7r,8t-dihydroxy-9t,10t-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene), on BRCA-1 levels and cell cycle kinetics were determined in MCF-7 breast cancer cells. Exposure of asynchronous MCF-7 cells for 72 hours to a non-cytotoxic dose of 0.5 μM B[a]P triggered a three-fold reduction in BRCA-1 protein. In MCF-7 cells resistant. (20% to 30%) to genotoxic concentrations of B[a]P (1 to 5 μM), the loss of BRCA-1 protein was coupled with pausing in S-phase and G2/M, and accumulation of p53, mdm2 and p21. Treatment of MCF-7 cells synchronized in S-phase (72%) with B[a]P prolonged the arrest in S-phase, although this checkpoint was transient since cells resumed to G2/M after 12 hours with reduced levels of BRCA-1. In these cells, levels of p53 were increased, whereas the cellular content of p21 remained unaltered. In contrast, the co-treatment with the AhR antagonist, α-naphthoflavone (ANF), abrogated the deleterious effects of B[a]P on BRCA-1 expression, while preventing the accumulation of p53 and disruption of cell cycle profile. These findings suggest that the AhR mediated the inverse expression patterns of BRCA-1 and p53 upon exposure to B[a]P. The treatment with BPDE induced S-phase arrest and reduced BRCA-1 mRNA levels. The negative effects of BPDE on BRCA-1 expression were not transient since removal of BPDE did not allow complete reversal of the repression. These cumulative data suggest that the B[a]P metabolite, BPDE, may play a key role in disruption of BRCA-1 expression and cell cycle kinetics in breast epithelial cells.