β4 Integrin Amplifies ErbB2 Signaling to Promote Mammary Tumorigenesis

Wenjun Guo, Yuliya Pylayeva, Angela Pepe, Toshiaki Yoshioka, William J. Muller, Giorgio Inghirami, Filippo G. Giancotti

Research output: Contribution to journalArticle

328 Scopus citations

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 β4 integrin during ErbB2-mediated tumorigenesis, we introduced a targeted deletion of the β4 signaling domain into a mouse model of ErbB2-induced mammary carcinoma. Loss of β4 signaling suppresses mammary tumor onset and invasive growth. Ex vivo studies indicate that β4 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 β4 signaling domain enhances the efficacy of ErbB2-targeted therapy. These results indicate that β4 integrin promotes tumor progression by amplifying ErbB2 signaling and identify β4 as a potential target for molecular therapy of breast cancer.

Original languageEnglish (US)
Pages (from-to)489-502
Number of pages14
JournalCell
Volume126
Issue number3
DOIs
StatePublished - Aug 4 2006

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Guo, W., Pylayeva, Y., Pepe, A., Yoshioka, T., Muller, W. J., Inghirami, G., & Giancotti, F. G. (2006). β4 Integrin Amplifies ErbB2 Signaling to Promote Mammary Tumorigenesis. Cell, 126(3), 489-502. https://doi.org/10.1016/j.cell.2006.05.047