Met and c-Src cooperate to compensate for loss of epidermal growth factor receptor kinase activity in breast cancer cells.
Cancer Res
; 68(9): 3314-22, 2008 May 01.
Article
em En
| MEDLINE
| ID: mdl-18451158
ABSTRACT
Breast cancers are not responsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), although 30% of breast cancers overexpress EGFR. The mechanism of intrinsic resistance to EGFR TKIs in breast cancer is the focus of current studies. Here, we observed that EGFR remains tyrosine phosphorylated in breast cancer cells that proliferate in the presence of EGFR TKIs. In one such cell line, SUM229, inhibiting c-Src kinase activity with either a dominant-negative c-Src or a c-Src TKI decreased EGFR phosphorylation on Tyr(845), Tyr(992), and Tyr(1086) in the presence of EGFR TKIs. Conversely, overexpressing wild-type (wt) c-Src in the EGFR TKI-sensitive breast cancer cell line SUM149 increased EGFR kinase-independent EGFR tyrosine phosphorylation. In addition, in the presence of EGFR TKIs, inhibiting c-Src kinase activity decreased cell growth in SUM229 cells, and overexpressing wt-c-Src increased cell growth in SUM149 cells. We identified the receptor tyrosine kinase Met to be responsible for activating c-Src in SUM229 cells. Inhibiting Met kinase activity with a small molecule inhibitor decreased c-Src phosphorylation and kinase activation. In addition, inhibiting Met kinase activity in SUM229 cells decreased EGFR tyrosine phosphorylation and growth in the presence of EGFR TKIs. Stimulating Met kinase activity in SUM149 cells with hepatocyte growth factor increased EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs. These data suggest a Met/c-Src-mediated signaling pathway as a mediator of EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Proteínas Proto-Oncogênicas pp60(c-src)
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Proteínas Proto-Oncogênicas c-met
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Receptores ErbB
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos