title: ARF1 regulates the Rho/MLC pathway to control EGF-dependent breast cancer cell invasion.
abstract: Invasion of tumor cells is a key step in metastasis that depends largely on the ability of these cells to degrade the extracellular matrix. Although we have showed that the GTPase ADP-ribosylation factor 1 (ARF1) is overexpressed in highly invasive breast cancer cell lines and that epidermal growth factor stimulation can activate this ARF isoform to regulate migration as well as proliferation, the role of this small GTP-binding protein has not been addressed in the context of invasiveness. Here we report that modulation of ARF1 expression and activity markedly impaired the ability of M.D. Anderson-metastatic breast-231 cells, a prototypical highly invasive breast cancer cell line, to degrade the extracellular matrix by controlling metalloproteinase-9 activity. In addition, we demonstrate that this occurs through inhibition of invadopodia maturation and shedding of membrane-derived microvesicles, the two key structures involved in invasion. To further define the molecular mechanisms by which ARF1 controls invasiveness, we show that ARF1 acts to modulate RhoA and RhoC activity, which in turn affects myosin light-chain (MLC) phosphorylation. Together our findings underscore for the first time a key role for ARF1 in invasion of breast cancer cells and suggest that targeting the ARF/Rho/MLC signaling axis might be a promising strategy to inhibit invasiveness and metastasis.
authors.affiliation: Department of Pharmacology and Membrane Protein Research Group (GEPROM), Faculty of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schlienger
authors.forename: Shirley
authors.initials: S
authors.lastname: Campbell
authors.forename: Audrey
authors.initials: A
authors.lastname: Claing
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000502:physiology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D018994:Myosin Light Chains; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D054460:rho-Associated Kinases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D020823:ADP-Ribosylation Factor 1