β4 integrin amplifies erbB2 signaling to promote mammary tumorigenesis Journal Article
| Authors: | Guo, W.; Pylayeva, Y.; Pepe, A.; Yoshioka, T.; Muller, W. J.; Inghirami, G.; Giancotti, F. G. |
| Article Title: | β4 integrin amplifies erbB2 signaling to promote mammary tumorigenesis |
| 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. © 2006 Elsevier Inc. All rights reserved. |
| Keywords: | signal transduction; controlled study; gene deletion; mutation; cancer growth; drug efficacy; nonhuman; drug targeting; protein domain; protein function; cell proliferation; animal cell; mouse; animals; mice; animal tissue; cells, cultured; stat3 protein; transcription initiation; epidermal growth factor receptor 2; animal experiment; animal model; cancer model; mice, transgenic; cell transformation, neoplastic; cancer invasion; breast carcinoma; carcinoma; stat3 transcription factor; cell polarity; protein structure, tertiary; receptor, erbb-2; epithelium; up-regulation; disease models, animal; ex vivo study; cell adhesion; breast carcinogenesis; macromolecular substances; mammary neoplasms, experimental; beta4 integrin; integrin beta4; jnk mitogen-activated protein kinases; protein c jun |
| Journal Title: | Cell |
| Volume: | 126 |
| Issue: | 3 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2006-08-11 |
| Start Page: | 489 |
| End Page: | 502 |
| Language: | English |
| DOI: | 10.1016/j.cell.2006.05.047 |
| PUBMED: | 16901783 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 162" - "Export Date: 4 June 2012" - "CODEN: CELLB" - "Source: Scopus" |
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