Identification and validation of novel ERBB2 (HER2, NEU) targets including genes involved in angiogenesis

Johannes Beckers, Felix Herrmann, Sandra Rieger, Alexei L. Drobyshev, Marion Horsch, Martin Hrabé De Angelis, Barbara Seliger

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2; synonyms HER2, NEU) encodes a transmembrane glycoprotein with tyrosine kinase-specific activity that acts as a major switch in different signal-transduction processes. ERBB2 amplification and overexpression have been found in a number of human cancers, including breast, ovary and kidney carcinoma. Our aim was to detect ERBB2-regulated target genes that contribute to its tumorigenic effect on a genomewide scale. The differential gene expression profile ERBB2-transfected and wild-type mouse fibroblasts was monitored employing DNA microarrays. Regulated expression of selected genes was verified by RT-PCR and validated by Western blot analysis. Genomewide gene expression profiling identified (i) known targets of ERBB2 signaling, (ii) genes implicated in tumorigenesis but so far not associated with ERBB2 signaling as well as (iii) genes not yet associated with oncogenic transformation, including novel genes without functional annotation. We also found that at least a fraction of coexpressed genes are closely linked on the genome. ERBB2 overexpression suppresses the transcription of antiangiogenic factors (e.g., Sparc, Timp3, Serpinf1) but induces expression of angiogenic factors (e.g., Klf5, Tnfaip2, Sema3c). Profiling of ERBB2-dependent gene regulation revealed a compendium of potential diagnostic markers and putative therapeutic targets. Identification of coexpressed genes that colocalize in the genome may indicate gene regulatory mechanisms that require further study to evaluate functional coregulation. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.).

Original languageEnglish (US)
Pages (from-to)590-597
Number of pages8
JournalInternational Journal of Cancer
Volume114
Issue number4
DOIs
StatePublished - Apr 20 2005
Externally publishedYes

Keywords

  • Angiogenesis
  • Erbb2
  • Erbb2 target pathway
  • Gene expression profiling
  • Gene regulation
  • Her2
  • In vitro model
  • Malignant transformation
  • Neu
  • Oncogene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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