Molecular mechanism of inhibitory aryl hydrocarbon receptor - Estrogen receptor/Sp1 cross talk in breast cancer cells

Shaheen Khan, Rola Barhoumi, Robert Burghardt, Shengxi Liu, Kyounghyun Kim, Stephen Safe

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The trifunctional carbamoylphosphate synthetase/aspartate transcarbamyltransferase/dihydroorotase (CAD) gene is hormone responsive in MCF-7 and ZR-75 breast cancer cells, and this response is inhibited by the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Estrogen-dependent induction of CAD mRNA and reporter gene activity in cells transfected with constructs (pCAD) containing hormone-responsive GC-rich CAD promoter inserts involves estrogen receptor α (ERα)/Sp1 interactions with these proximal GC-rich motifs. TCDD also inhibits hormone-induced transactivation in MCF-7 and ZR-75 cells transfected with pCAD constructs. The mechanism of inhibitory AhR-ERα/Sp1 cross talk was further investigated by chromatin immunoprecipitation (ChIP), and the results show that ERα/Sp1 and the AhR are constitutively bound to the CAD gene promoter and only minor changes are observed after treatment with 17β-estradiol, TCDD, or their combination. However, examination of interactions of these transcription factors by fluorescence resonance energy transfer shows that E2 enhances ERα-Sp1 interactions, whereas cotreatment with TCDD significantly decreases interaction of these proteins. These results suggest that inhibitory AhR-ERα/Sp1 cross talk is due, in part, to enhanced association of AhR and ERα (also determined by fluorescence resonance energy transfer), which coordinately dissociates ER and Sp1 and decreases ERα/Sp1-mediated transactivation, whereas remaining associated with the CAD promoter. This represents a novel interaction between two ligand activated receptors where one receptor inhibits activation of the second receptor.

Original languageEnglish (US)
Pages (from-to)2199-2214
Number of pages16
JournalMolecular Endocrinology
Volume20
Issue number9
DOIs
StatePublished - Aug 31 2006

Fingerprint

Receptor Cross-Talk
Aryl Hydrocarbon Receptors
Estrogen Receptors
Breast Neoplasms
Fluorescence Resonance Energy Transfer
Hormones
Transcriptional Activation
Dihydroorotase
Chromatin Immunoprecipitation
Ligases
Reporter Genes
Aspartic Acid
Genes
Estradiol
Estrogens
Transcription Factors
Ligands

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Molecular mechanism of inhibitory aryl hydrocarbon receptor - Estrogen receptor/Sp1 cross talk in breast cancer cells. / Khan, Shaheen; Barhoumi, Rola; Burghardt, Robert; Liu, Shengxi; Kim, Kyounghyun; Safe, Stephen.

In: Molecular Endocrinology, Vol. 20, No. 9, 31.08.2006, p. 2199-2214.

Research output: Contribution to journalArticle

Khan, Shaheen ; Barhoumi, Rola ; Burghardt, Robert ; Liu, Shengxi ; Kim, Kyounghyun ; Safe, Stephen. / Molecular mechanism of inhibitory aryl hydrocarbon receptor - Estrogen receptor/Sp1 cross talk in breast cancer cells. In: Molecular Endocrinology. 2006 ; Vol. 20, No. 9. pp. 2199-2214.
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