TY - JOUR
T1 - β4 Integrin Amplifies ErbB2 Signaling to Promote Mammary Tumorigenesis
AU - Guo, Wenjun
AU - Pylayeva, Yuliya
AU - Pepe, Angela
AU - Yoshioka, Toshiaki
AU - Muller, William J.
AU - Inghirami, Giorgio
AU - Giancotti, Filippo G.
N1 - Funding Information:
We thank D. Veach for synthesis of dasatinib and Gleevec, M. Sturniolo for experiments with Gleevec, J. Bromberg and P. Siegel for reagents and advice, G. Nolan and T. Sasaki for reagents, the Molecular Cytology Facility of MSKCC for technical help, and members of the Giancotti laboratory for discussions. This work was supported by NIH grants R37 CA58976 (to F.G.G.) and P30 CA08748 (to MSKCC). W.J.M. is supported by a Canada Research Chair in Molecular Oncology. F.G.G. wishes to dedicate this work to the memory of his mother, Marisa Giancotti, and all other women who have succumbed to breast cancer.
PY - 2006/8/4
Y1 - 2006/8/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2006.05.047
DO - 10.1016/j.cell.2006.05.047
M3 - Article
C2 - 16901783
AN - SCOPUS:33746764457
SN - 0092-8674
VL - 126
SP - 489
EP - 502
JO - Cell
JF - Cell
IS - 3
ER -