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Role of c-Src in human MCF7 breast cancer cell tumorigenesis

AuthorsGonzález, Lorena; Agulló-Ortuño, María Teresa ; García-Martínez, José Manuel ; Calcabrini, Annarica ; Gamallo, Carlos; Palacios, José; Aranda, Ana ; Martín-Pérez, Jorge
Issue Date2006
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 281(30): 20851-20864 (2006)
AbstractTo 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-Tyr397 autophosphorylation and to inhibition of Fak-Tyr925, 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 tumor development, a significant tumor regression was observed. 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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Identifiersdoi: 10.1074/jbc.M601570200
issn: 0021-9258
e-issn: 1083-351X
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