Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis.
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.
Guo
Wenjun
W
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA.
Pylayeva
Yuliya
Y
Pepe
Angela
A
Yoshioka
Toshiaki
T
Muller
William J
WJ
Inghirami
Giorgio
G
Giancotti
Filippo G
FG
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002448:Cell Adhesion / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D039663:Integrin beta4; D048031:JNK Mitogen-Activated Protein Kinases; D046911:Macromolecular Substances; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor