GEF-H1 drives breast cancer cells to tumor formation and metastasis

Abstract

Rho GTPases are involved in several biological and pathological processes, including gene transcription, cell polarity, migration and invasion. Rho guanine nucleotide exchange factor-H1 (GEF-H1) is the unique RhoA activator that binds to microtubules and its localization and activity is regulated in part by fibronectin-binding integrins. The aim of this work is to investigate the role of GEF-H1 in breast cancer progression. We report that the expression of GEF-H1 is higher in human breast cancer biopsies than in normal tissue. Furthermore, the expression of GEF-H1 is higher in breast cancer cell lines than in non-tumoral cell lines. We observed a significant reduction in the number of focal adhesions, stress fibers formation and altered downstream signaling in GEF-H1 knockout (KO) breast cancer cell lines, resulting in decreased cell proliferation, migration, adhesion and invasion. In addition, orthotopic implantation of GEF-H1 KO cells into mammary fat pads of Balb/c mice showed a significant delay in tumor formation and lung metastasis development compared to control breast cancer cells. These results suggest that activation of GEF-H1/RhoA mediates cytoskeletal remodeling and signaling pathways involved in cell proliferation, migration, and invasion of breast cancer cells. In vivo assays and human biopsy studies suggest that GEF-H1 expression indeed contributes to breast tumor progression and could be postulated as a potential biomarker.