The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen

Jennifer K. Hockings, Patricia A. Thorne, Michael Q. Kemp, Sherif S. Morgan, Ornella Selmin, Donato Romagnolo

Research output: Contribution to journalArticle

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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-α (ERα) 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 ERα-negative HeLa cells of ERα 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 ERα-binding region. These results suggest that the physical interaction between the unliganded AhR and the liganded ERα 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.

Original languageEnglish (US)
Pages (from-to)2224-2232
Number of pages9
JournalCancer Research
Volume66
Issue number4
DOIs
StatePublished - Feb 15 2006

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Aromatic Hydrocarbons
Transcriptional Activation
Estrogens
Ligands
Estrogen Receptors
Benzo(a)pyrene
Breast Neoplasms
Endocrine Disruptors
Tobacco Smoke Pollution
Mutation
Transcription Factor AP-1
Xenobiotics
Acetylation
HeLa Cells
Genetic Promoter Regions
Protein Binding
Carcinogens
Food
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen. / Hockings, Jennifer K.; Thorne, Patricia A.; Kemp, Michael Q.; Morgan, Sherif S.; Selmin, Ornella; Romagnolo, Donato.

In: Cancer Research, Vol. 66, No. 4, 15.02.2006, p. 2224-2232.

Research output: Contribution to journalArticle

Hockings, Jennifer K. ; Thorne, Patricia A. ; Kemp, Michael Q. ; Morgan, Sherif S. ; Selmin, Ornella ; Romagnolo, Donato. / The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen. In: Cancer Research. 2006 ; Vol. 66, No. 4. pp. 2224-2232.
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