Beta 4 Integrin Amplifies ErbB2 Signaling to Promote Mammary Tumorigenesis

Cell. 2006 Aug 11;126(3):489-502. doi: 10.1016/j.cell.2006.05.047.

Abstract

Amplification of the ErbB2 locus, which encodes a receptor tyrosine kinase, is common in aggressive breast tumors and correlates with poor prognosis. The mechanisms underlying ErbB2-mediated breast carcinoma progression remain incompletely defined. To examine the role of the signaling and cell-adhesion receptor beta 4 integrin during ErbB2-mediated tumorigenesis, we introduced a targeted deletion of the beta 4 signaling domain into a mouse model of ErbB2-induced mammary carcinoma. Loss of beta 4 signaling suppresses mammary tumor onset and invasive growth. Ex vivo studies indicate that beta 4 forms a complex with ErbB2 and enhances activation of the transcription factors STAT3 and c-Jun. STAT3 contributes to disruption of epithelial adhesion and polarity, while c-Jun is required for hyperproliferation. Finally, deletion of the beta 4 signaling domain enhances the efficacy of ErbB2-targeted therapy. These results indicate that beta 4 integrin promotes tumor progression by amplifying ErbB2 signaling and identify beta 4 as a potential target for molecular therapy of breast cancer.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma / genetics
  • Carcinoma / metabolism*
  • Carcinoma / physiopathology
  • Cell Adhesion / genetics
  • Cell Polarity / genetics
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Integrin beta4 / genetics
  • Integrin beta4 / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Macromolecular Substances / metabolism
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / physiopathology
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Protein Structure, Tertiary / genetics
  • Receptor, ErbB-2 / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics*
  • Up-Regulation / genetics

Substances

  • Integrin beta4
  • Macromolecular Substances
  • STAT3 Transcription Factor
  • Receptor, ErbB-2
  • JNK Mitogen-Activated Protein Kinases