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Sci. Signal., 2 October 2012
Vol. 5, Issue 244, p. ra71
[DOI: 10.1126/scisignal.2002962]

RESEARCH ARTICLES

The Rho Exchange Factors Vav2 and Vav3 Control a Lung Metastasis–Specific Transcriptional Program in Breast Cancer Cells

Carmen Citterio1,2*, Mauricio Menacho-Márquez1,2*, Ramón García-Escudero3, Romain M. Larive1,2, Olga Barreiro4, Francisco Sánchez-Madrid4, Jesús M. Paramio3, and Xosé R. Bustelo1,2{dagger}

1 Centro de Investigación del Cáncer, CSIC-University of Salamanca, 37007 Salamanca, Spain.
2 Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007 Salamanca, Spain.
3 Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain.
4 Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain.

* These authors contributed equally to this work.

Abstract: The guanosine triphosphatases of the Rho and Rac subfamilies regulate protumorigenic pathways and are activated by guanine nucleotide exchange factors (Rho GEFs), which could be potential targets for anticancer therapies. We report that two Rho GEFs, Vav2 and Vav3, play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and many of the steps involved in lung-specific metastasis. The involvement of Vav proteins in these processes did not correlate with Rac1 and RhoA activity or cell migration, implying the presence of additional biological programs. Microarray analyses revealed that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. Furthermore, the abundance of Vav-regulated transcripts was modulated by Rac1-dependent and Rac1-independent pathways. This transcriptome encoded therapeutically targetable proteins that played nonredundant roles in primary tumorigenesis and lung-specific metastasis, such as integrin-linked kinase (Ilk), the transforming growth factor–β family ligand inhibin βA, cyclooxygenase-2, and the epithelial cell adhesion molecule Tacstd2. It also contained gene signatures that predicted disease outcome in breast cancer patients. These results identify possible targets for treating breast cancer and lung metastases and provide a potential diagnostic tool for clinical use.

{dagger} To whom correspondence should be addressed. E-mail: xbustelo{at}usal.es

Citation: C. Citterio, M. Menacho-Márquez, R. García-Escudero, R. M. Larive, O. Barreiro, F. Sánchez-Madrid, J. M. Paramio, X. R. Bustelo, The Rho Exchange Factors Vav2 and Vav3 Control a Lung Metastasis–Specific Transcriptional Program in Breast Cancer Cells. Sci. Signal. 5, ra71 (2012).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins.
M. Barreira, S. Fabbiano, J. R. Couceiro, E. Torreira, J. L. Martinez-Torrecuadrada, G. Montoya, O. Llorca, and X. R. Bustelo (2014)
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Rho GEFs and Cancer: Linking Gene Expression and Metastatic Dissemination.
L. Barrio-Real and M. G. Kazanietz (2012)
Science Signaling 5, pe43
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