The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells

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, andmany 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 Vavregulated transcripts wasmodulated 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 adhesionmolecule 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.X.R.B.’s work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2009-07172 and RD06/0020/0001), the Castilla-León Autonomous Government (GR97), the 7th Framework European Union Program (FP7-HEALTH-2007-A-201862), and the Spanish Association Against Cancer. A portion of X.R.B.’s funding comes from the European Regional Development Fund. Work in J.M.P.’s laboratory is partially supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2006-00121 and RD06/0020/0029) and the Madrid Autonomous Government (S2006/BIO-0232). C.C.’s and M.M.-M.’s salaries were partially supported by the JAE-Doc program, the Spanish National Research Council, the RD06/0020/0001 grant, and the European Regional Development Fund.Peer Reviewe