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The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Hockings, Jennifer K. Thorne, Patricia A. Kemp, Michael Q. Morgan, Sherif S. Selmin, Ornella Romagnolo, Donato F. |
| Copyright Year | 2006 |
| Abstract | In sporadic breast cancers, BRCA-1 expression is down-regulated in the absence of mutations in the BRCA-1 gene. This suggests that disruption of BRCA-1 expression may contribute to the onset of mammary tumors. Environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo(a)pyrene [B(a)P] and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to act as endocrine disruptors and tumor promoters. In previous studies, we documented that estrogen (E2) induced BRCA-1 transcription through the recruitment of an activator protein-1/estrogen receptor-alpha (ER alpha) complex to the proximal BRCA-1 promoter. Here, we report that activation of BRCA-1 transcription by E2 requires occupancy of the BRCA-1 promoter by the unliganded aromatic hydrocarbon receptor (AhR). The stimulatory effects of E2 on BRCA-1 transcription are counteracted by (a) cotreatment with the AhR antagonist 3'-methoxy-4'-nitroflavone; (b) transient expression in ER alpha-negative HeLa cells of ER alpha lacking the protein-binding domain for the AhR; and (c) mutation of two consensus xenobiotic-responsive elements (XRE, 5'-GCGTG-3') located upstream of the ER alpha-binding region. These results suggest that the physical interaction between the unliganded AhR and the liganded ER alpha plays a positive role in E2-dependent activation of BRCA-1 transcription. Conversely, we show that the AhR ligands B(a)P and TCDD abrogate E2-induced BRCA-1 promoter activity. The repressive effects of TCDD are paralleled by increased recruitment of the liganded AhR and HDAC1, reduced occupancy by p300, SRC-1, and diminished acetylation of H4 at the BRCA-1 promoter region flanking the XREs. We propose that the ligand status of the AhR modulates activation of the BRCA-1 promoter by estrogen. |
| Starting Page | 163 |
| Ending Page | 164 |
| Page Count | 2 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/66/4/2224.full.pdf |
| PubMed reference number | 16489025v1 |
| Volume Number | 66 |
| Issue Number | 4 |
| Journal | Cancer research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 3'-methoxy-4'-nitroflavone Animal Mammary Neoplasms Aryl Hydrocarbon Receptor Benzo(a)pyrene Binding (Molecular Function) Combined Modality Therapy Cooking (activity) Dioxins Endocrine System Diseases Estradiol Estrogens Flank (surface region) Hydrocarbons Hydrocarbons, Aromatic Ligands Mutation NCOA1 protein, human Promoter Regions, Genetic Tetrachlorodibenzodioxin Tobacco Smoke Pollution Transcription, Genetic Transcriptional Activation estrogen receptor alpha, human pediatric intracranial germ cell brain tumor |
| Content Type | Text |
| Resource Type | Article |
