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

B. D. Jeffy, E. J. Chen, J. M. Gudas, Donato Romagnolo

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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, BPDF, may play a key role in disruption of BRCA-1 expression and cell cycle kinetics in breast epithelial cells. Neoplasia (2000) 2, 460-470.

Original languageEnglish (US)
Pages (from-to)460-470
Number of pages11
JournalNeoplasia
Volume2
Issue number5
StatePublished - 2000

Fingerprint

Benzo(a)pyrene
MCF-7 Cells
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Cell Cycle
Aromatic Hydrocarbons
S Phase
S Phase Cell Cycle Checkpoints
Proteins
Breast
Epithelial Cells
Breast Neoplasms
Ligands
Messenger RNA
Neoplasms

Keywords

  • Benzo[a]pyrene
  • BPDE
  • BRCA-1
  • Cell cycle kinetics
  • P53
  • Sporadic breast cancer

ASJC Scopus subject areas

  • Cancer Research

Cite this

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. / Jeffy, B. D.; Chen, E. J.; Gudas, J. M.; Romagnolo, Donato.

In: Neoplasia, Vol. 2, No. 5, 2000, p. 460-470.

Research output: Contribution to journalArticle

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abstract = "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, BPDF, may play a key role in disruption of BRCA-1 expression and cell cycle kinetics in breast epithelial cells. Neoplasia (2000) 2, 460-470.",
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AU - Romagnolo, Donato

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AB - 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, BPDF, may play a key role in disruption of BRCA-1 expression and cell cycle kinetics in breast epithelial cells. Neoplasia (2000) 2, 460-470.

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