Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Activation of the aromatic hydrocarbon receptor pathway is not sufficient for transcriptional repression of BRCA-1: requirements for metabolism of benzo[a]pyrene to 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

Authors: Jeffy, Brandon D; Chirnomas, Ryan B; Chen, Eddy J; Gudas, Jean M; Romagnolo, Donato F

Published In Cancer Res, (2002 Jan 1)

Abstract: Reduction of BRCA-1 expression through nonmutational events may be a predisposing event in the onset of sporadic breast cancer. In this study, we investigated the mechanisms through which the environmental carcinogen benzo[a]pyrene (B[a]P) lowered BRCA-1 mRNA levels in breast cancer MCF-7 cells. We report that B[a]P does not compromise the stability of BRCA-1 mRNA, but represses transcriptional activity of a 1.69-kb BRCA-1 (pGL3-BRCA-1) promoter fragment that contains both exon-1A and exon-1B transcription start sites. The loss of BRCA-1 promoter activity was accompanied by accumulation of CYP1A1 and BAX-alpha mRNA and p53 and p21 protein, whereas levels of Bcl-2 mRNA were reduced. The aromatic hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is not metabolized, did not affect BRCA-1 promoter activity or the cellular levels of BRCA-1 and p53 protein, but it did induce a CYP1A1-like promoter. Conversely, treatment with the B[a]P metabolite 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) repressed BRCA-1 promoter activity and protein, while increasing p53 and p21 protein levels. Transient expression of dominant-negative p53 ((175)Arg-->His) counteracted the detrimental effects of BPDE on BRCA-1 promoter activity and protein levels. Similarly, treatment with B[a]P, TCDD, or BPDE failed to repress transcription from the pGL3-BRCA-1 construct transfected into ZR75.1 breast cancer cells containing mutated p53 ((152)Pro-->Leu). We conclude that activation of the aromatic hydrocarbon receptor is not sufficient for down-regulation of BRCA-1 transcription, which is, however, inhibited by the B[a]P metabolite BPDE through a p53-dependent pathway.

PubMed ID: 11782367 Exiting the NIEHS site

MeSH Terms: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/metabolism*; 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/toxicity; BRCA1 Protein/biosynthesis*; BRCA1 Protein/genetics; Benzo(a)pyrene/metabolism*; Benzo(a)pyrene/toxicity; Biotransformation; Breast Neoplasms/chemically induced; Breast Neoplasms/genetics*; Breast Neoplasms/metabolism*; Carcinogens/metabolism*; Carcinogens/toxicity; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic/drug effects; Gene Expression Regulation, Neoplastic/physiology; Genes, BRCA1/drug effects; Humans; Promoter Regions, Genetic/drug effects; RNA, Messenger/biosynthesis; RNA, Messenger/genetics; Receptors, Aryl Hydrocarbon/metabolism; Receptors, Aryl Hydrocarbon/physiology*; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/drug effects; Signal Transduction/physiology; Tetrachlorodibenzodioxin/toxicity; Transcription, Genetic/drug effects*; Transcription, Genetic/physiology; Tumor Cells, Cultured; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/physiology

Back
to Top