title: The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells.
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.
authors.affiliation: Centro de Investigación del Cáncer, CSIC-University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Citterio
authors.forename: Mauricio
authors.initials: M
authors.lastname: Menacho-Márquez
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.forename: Romain M
authors.initials: RM
authors.lastname: Larive
authors.forename: Olga
authors.initials: O
authors.lastname: Barreiro
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D020830:rac1 GTP-Binding Protein / Q000235:genetics; D000099200:Scaffold Protein ILK
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D051546:Cyclooxygenase 2; D028322:Inhibin-beta Subunits; D017346:Protein Serine-Threonine Kinases; D051567:Proto-Oncogene Proteins c-vav; D020830:rac1 GTP-Binding Protein; D000099200:Scaffold Protein ILK; C499380:TACSTD2 protein, human; C093651:VAV2 protein, human; C496621:VAV3 protein, human; C103008:inhibin beta A subunit