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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]pyrene¹

Cancer Biology Interdisciplinary Program [B. D. J., D. F. R.], Laboratory of Mammary Gland Biology, Department of Nutritional Sciences [B. D. J., R. B. C., D. F. R.], The University of Arizona, Tucson, Arizona 85721; Amgen Inc., Thousand Oaks, California 91320 [E. J. C., J. M. G.]; and Southwest Environmental Health Sciences Center, The University of Arizona, Tucson, Arizona 85721 [D. F. R.]

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- 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 (¹⁷⁵ArgHis) 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 (¹⁵²ProLeu). 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.

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