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.

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

“…For example, the GEF Tiam1 is highly expressed in high-grade breast tumors, where it mediates migration and invasion (50,51). Vav1 and Vav3 are overexpressed in breast tumors and regulate lung metastasis (52). Likewise, P-Rex is highly expressed in metastatic breast tumors and mediates motility and tumorigenesis driven by ErbB receptors (53).…”

Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

“…68). Moreover, Vav2 recently was shown to be required for lungspecific metastasis of breast cancer 69 . As broad inhibition of c-Met by specific tyrosine kinase inhibitors may lead to tumour resistance, such as is seen in the clinic with other RTK inhibitors, targeting localized effectors, such as Vav2 in c-Met-driven invasive breast tumours, may represent alternative therapeutic solutions.…”

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

“…To this end, tissues were extracted, fixed in 4% paraformaldehyde (Sigma), cut in 2-3-mm-thick sections, and stained with haematoxylin/eosin. Proliferation and angiogenesis were monitored by immunohistochemical staining of tumour section with antibodies to Ki67 and CD31, respectively 18,51 . Apoptotic cells were detected using either TUNEL (TdTmediated dUTP nick end labelling) labelling or cleaved caspase 3 immunostaining 18 .…”