Vav proteins maintain epithelial traits in breast cancer cells using miR-200c -dependent and independent mechanisms

The bidirectional regulation of epithelial–mesenchymal transitions(EMT) is key in tumorigenesis. Rho GTPasesregulate this process via canonical pathways that impinge on the stability of cell-to-cell contacts, cytoskeletal dynamics, and cell invasiveness. Here, we report that the Rho GTPaseactivators Vav2and Vav3utilize a new Rac1-dependent and miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage a mir-200c-independent expression prometastatic program that maintains epithelial cell traits only under 3D culture conditions. Consistent with this, the depletion of endogenous Vav proteins triggers mesenchymalfeatures in epithelioid breast cancer cells. Conversely, the ectopic expressionof an active version of Vav2promotes mesenchymal-epithelial transitionsusing E-cadherin-dependent and independent mechanisms depending on the mesenchymalbreast cancer cell line used. In silico analyses suggest that the negative Vav anti-EMT pathway is operative in luminal breast tumors. Gene signaturesfrom the Vav-associated proepithelial and prometastatic programs have prognostic value in breast cancer patients.