A negative feedback regulatory loop associates the tyrosine kinase receptor ERBB2 and the transcription factor GATA4 in breast cancer cells

Guoqiang Hua, Bing Zhu, Fréderic Rosa, Nicolas Deblon, José Adélaïde, Brigitte Kahn-Perlès, Daniel Birnbaum, Jean Imbert

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Overexpression of the ERBB2 gene, linked to genomic and transcriptional amplifications, is a poor prognosis indicator in 25% to 30% of breast cancers. In contrast to some well-documented genomic amplifications, molecular mechanisms leading to ERBB2 transcriptional overexpression remain poorly characterized. Gene expression analyses of breast cancer have characterized distinct transcriptional signatures allowing a molecular classification of breast carcinoma. Coexpression of the ERBB2 and GATA4 genes was originally observed in tumors. Both genes are essential for cardiovascular development and GATA4 has been proposed to control the transcription of critical genes for the differentiation and the function of myocardium. We determined that ERBB2-targeted small interfering RNA repressed both ERBB2 and GATA4 genes, whereas GATA4-targeted small interfering RNA repressed GATA4 and activated ERBB2 transcription. Transfected GATA4-expressing construct repressed ERBB2 promoter. Phylogenetic foot printing revealed multiple putative GATA4 binding sites conserved in mammals within the ERBB2 promoter region. Chromatin immunoprecipitation showed that GATA4 binds specifically to several ERBB2 gene noncoding regions. Electrophoretic mobility shift assay revealed GATA4 binding to a well-conserved consensus motif. Site-directed mutagenesis confirmed the role of this new regulatory element for the activity of the ERBB2 gene enhancer. In agreement with a repressor role of GATA4 on ERBB2 gene expression balanced by ERBB2 activation of the GATA4 gene, a negative correlation between the relative levels of ERBB2 and GATA4 mRNA was observed in breast cancer cell lines and breast tumor samples. We propose that the negative feedback loop linking ERBB2 and GATA4 plays a role in the transcriptional dysregulation of ERBB2 gene expression in breast cancer.

Original languageEnglish (US)
Pages (from-to)402-414
Number of pages13
JournalMolecular Cancer Research
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2009

Fingerprint

GATA4 Transcription Factor
Receptor Protein-Tyrosine Kinases
Breast Neoplasms
Genes
Gene Expression
Small Interfering RNA
Printing
Chromatin Immunoprecipitation
Essential Genes
Electrophoretic Mobility Shift Assay
Site-Directed Mutagenesis
Genetic Promoter Regions
Transcriptional Activation
Foot
Mammals
Myocardium
Binding Sites
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

A negative feedback regulatory loop associates the tyrosine kinase receptor ERBB2 and the transcription factor GATA4 in breast cancer cells. / Hua, Guoqiang; Zhu, Bing; Rosa, Fréderic; Deblon, Nicolas; Adélaïde, José; Kahn-Perlès, Brigitte; Birnbaum, Daniel; Imbert, Jean.

In: Molecular Cancer Research, Vol. 7, No. 3, 01.03.2009, p. 402-414.

Research output: Contribution to journalArticle

Hua, Guoqiang ; Zhu, Bing ; Rosa, Fréderic ; Deblon, Nicolas ; Adélaïde, José ; Kahn-Perlès, Brigitte ; Birnbaum, Daniel ; Imbert, Jean. / A negative feedback regulatory loop associates the tyrosine kinase receptor ERBB2 and the transcription factor GATA4 in breast cancer cells. In: Molecular Cancer Research. 2009 ; Vol. 7, No. 3. pp. 402-414.
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