Abstract
The bidirectional regulation of epithelial–mesenchymal transitions (EMT) is key in tumorigenesis. Rho GTPases regulate 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 GTPase activators Vav2 and Vav3 utilize 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 mesenchymal features in epithelioid breast cancer cells. Conversely, the ectopic expression of an active version of Vav2 promotes mesenchymal-epithelial transitions using E-cadherin-dependent and independent mechanisms depending on the mesenchymal breast cancer cell line used. In silico analyses suggest that the negative Vav anti-EMT pathway is operative in luminal breast tumors. Gene signatures from the Vav-associated proepithelial and prometastatic programs have prognostic value in breast cancer patients.
Highlights
The epithelial–mesenchymal transitions (EMT) is associated with the acquisition of a variety of malignant traits in cancer cells such as motility, These authors contributed : L
This phenotype, which is even more extreme than that observed in the case of KD2/3 cells, resembles cases of partial EMT previously found in other 3D models. This phenotype is not observed in Ptgs2depleted 4T1 cells (Fig. 6d). These results suggest that Vav proteins can utilize independent mechanisms to maintain the epithelial phenotype in 2D and 3D conditions
Given that KD-Itgb6 and KD-Itga8 cells do not show any significant defect in primary tumorigenesis or metastasis (Fig. 6a), these results indicate that the induction of this EMT-like process under 3D culture conditions does not favor per se the metastatic potential of these cells
Summary
The EMT is associated with the acquisition of a variety of malignant traits in cancer cells such as motility, These authors contributed : L. Spain 3 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC-University of Salamanca, 37007 Salamanca, Spain 4 CIEMAT, 28040 Madrid, Spain invasiveness, metastasis, stemcellness, and chemoresistance [1,2,3,4,5] This process can be regulated by multiple signaling and regulatory elements that include, among many others, the transforming growth factor β (TGFβ) pathway, protein tyrosine kinases, the Ras–Raf–ERK signaling cascade, the PI3Kα–mTOR axis, the Rho GTPase family, noncoding RNAs, and transcriptional factors such as those belonging to the Snail, Twist, and Zeb families [1, 4, 6].
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