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.

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.

• Authors: Brandon D Jeffy, Ryan B Chirnomas, Eddy J Chen, Jean M Gudas, Donato F Romagnolo
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 1 Pg. 113-21 (Jan 01 2002) ISSN: 0008-5472 [Print] United States
• PMID: 11782367 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BRCA1 Protein
• Carcinogens
• Polychlorinated Dibenzodioxins
• RNA, Messenger
• Receptors, Aryl Hydrocarbon
• Tumor Suppressor Protein p53
• Benzo(a)pyrene
• 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide

Topics

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