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J. Biol. Chem., Vol. 281, Issue 30, 20851-20864, July 28, 2006

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Role of c-Src in Human MCF7 Breast Cancer Cell Tumorigenesis^*

Lorena González¹, María Teresa Agulló-Ortuño², José Manuel García-Martínez³, Annarica Calcabrini, Carlos Gamallo, José Palacios^¶4, Ana Aranda, and Jorge Martín-Pérez⁵

From the Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Arturo Duperier 4, 28029 Madrid, Spain, the Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy, and the ^¶Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain

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-Tyr³⁹⁷ autophosphorylation and to inhibition of Fak-Tyr⁹²⁵, p130^CAS, and paxillin phosphorylation. An increased association of total Src with Fak and a decreased interaction of p130^CAS 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 p27^Kip1 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.

Received for publication, February 17, 2006

^* This work was supported by Grants from Ministerio de Educación y Ciencia (SAF2003-02188) and Fondo de Investigaciones Sanitarias (01/1316, 04/0682, and 03C03/10). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental materials.

¹ Supported by a fellowship from Fundación Carolina and by Grant FIS 03C03/10.

² Supported by the FIS 03C03/10 Grant.

³ Supported by a fellowship from FIS and by Grant SAF2003-02188.

⁴ Member of GEICAM.

⁵ Member of GEICAM. To whom correspondence should be addressed. Tel.: 34915854416; Fax: 34915854401; E-mail: jmartin{at}iib.uam.es.

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