Effects of HER2 overexpression on cell signaling networks governing proliferation and migration

Mol Syst Biol. 2006;2:54. doi: 10.1038/msb4100094. Epub 2006 Oct 3.

Abstract

Although human epidermal growth factor receptor 2 (HER2) overexpression is implicated in tumor progression for a variety of cancer types, how it dysregulates signaling networks governing cell behavioral functions is poorly understood. To address this problem, we use quantitative mass spectrometry to analyze dynamic effects of HER2 overexpression on phosphotyrosine signaling in human mammary epithelial cells stimulated by epidermal growth factor (EGF) or heregulin (HRG). Data generated from this analysis reveal that EGF stimulation of HER2-overexpressing cells activates multiple signaling pathways to stimulate migration, whereas HRG stimulation of these cells results in amplification of a specific subset of the migration signaling network. Self-organizing map analysis of the phosphoproteomic data set permitted elucidation of network modules differentially regulated in HER2-overexpressing cells in comparison with parental cells for EGF and HRG treatment. Partial least-squares regression analysis of the same data set identified quantitative combinations of signals within the networks that strongly correlate with cell proliferation and migration measured under the same battery of conditions. Combining these modeling approaches enabled association of epidermal growth factor receptor family dimerization to activation of specific phosphorylation sites, which appear to most critically regulate proliferation and/or migration.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Algorithms
  • Breast / cytology*
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cell Division / physiology
  • Cell Line / drug effects
  • Cell Line / metabolism
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Dimerization
  • Epidermal Growth Factor / pharmacology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • ErbB Receptors / chemistry
  • ErbB Receptors / genetics
  • ErbB Receptors / physiology
  • Female
  • Gene Expression
  • Genes, erbB-1
  • Genes, erbB-2
  • Humans
  • Least-Squares Analysis
  • Mass Spectrometry
  • Neuregulin-1 / pharmacology
  • Phosphorylation / drug effects
  • Phosphotyrosine / physiology*
  • Protein Processing, Post-Translational* / drug effects
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / physiology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction* / drug effects

Substances

  • Neuregulin-1
  • Recombinant Fusion Proteins
  • Phosphotyrosine
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, ErbB-2