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Papers In Press, published online ahead of print May 25, 2006
Instituto de Investigaciones Biomedicas, CSIC, Madrid, Madrid E-28029
Corresponding Author: jmartin{at}iib.uam.es
To study the role of c-Src in breast cancer tumorigenesis we generated a cell line derived from MCF7 carrying an inducible dominant negative c-Src (c-SrcDN: K295M/Y527F) under tetracycline control (Tet-On system). c-SrcDN expression caused phenotypic changes, relocation of c-Src, Fak and paxillin, and loss of correct actin fiber assembly. These alterations were coupled to increased Fak-Y397 autophosphorylation and to inhibition of Fak-Y925, p130CAS, and paxillin phosphorylation. An increased association of total Src with Fak and a decreased interaction of p130CAS and p85-PI3K with Fak were also observed. SrcDN inhibited cell attachment, spreading, and migration. Serum and EGF-induced stimulation of cell proliferation and Akt phosphorylation were also significantly reduced by SrcDN, whereas p27Kip1 expression was increased. Consistently, silencing c-Src expression by siRNA in MCF7 cells significantly reduced cell migration, attachment, spreading and proliferation. Inoculation of MCF7 cells carrying inducible SrcDN to nude mice generated tumors. However, doxycycline administration to mice significantly reduced tumorigenesis, and when doxycycline treatment was installed after tumors development, a significant tumor regression. In both situations, inhibition of tumorigenesis was associated with decreased Ki67 staining and increased apoptosis in tumors. These data undoubtedly demonstrate the relevance of the Src/Fak complex in breast cancer tumorigenesis.
J. Biol. Chem, 10.1074/jbc.M601570200
Submitted on February 17, 2006
Revised on January 1, 1998
Accepted on May 25, 2006
Role of c-SRC in human MCF7 breast cancer cell tumorigenesis
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