title: SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer.
abstract: The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed 'mesenchymal' and 'amoeboid', with possible transitions between these modes. Here we show that the SCN4B gene, encoding for the β4 protein, initially characterized as an auxiliary subunit of voltage-gated sodium channels (NaV) in excitable tissues, is expressed in normal epithelial cells and that reduced β4 protein levels in breast cancer biopsies correlate with high-grade primary and metastatic tumours. In cancer cells, reducing β4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid-mesenchymal hybrid phenotype. This hyperactivated migration is independent of NaVand is prevented by overexpression of the intracellular C-terminus of β4. Conversely, SCN4B overexpression reduces cancer cell invasiveness and tumour progression, indicating that SCN4B/β4 represents a metastasis-suppressor gene.
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Bon
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Driffort
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gradek
authors.affiliation: Inflammation and Experimental Surgery Unit, CIBERehd, Murcia's BioHealth Research Institute IMIB-Arrixaca, Clinical University Hospital Virgen de la Arrixaca, E-30120 Murcia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Martinez-Caceres
authors.affiliation: Telomerase, Cancer and Aging Group, Hospital Virgen de la Arrixaca, E-30120 Murcia, Spain.
authors.forename: Monique
authors.initials: M
authors.lastname: Anchelin
authors.affiliation: Inflammation and Experimental Surgery Unit, CIBERehd, Murcia's BioHealth Research Institute IMIB-Arrixaca, Clinical University Hospital Virgen de la Arrixaca, E-30120 Murcia, Spain.
authors.forename: Pablo
authors.identifier: 0000-0002-9688-1804
authors.initials: P
authors.lastname: Pelegrin
authors.affiliation: Telomerase, Cancer and Aging Group, Hospital Virgen de la Arrixaca, E-30120 Murcia, Spain.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Cayuela
authors.affiliation: Cancéropôle du Grand Ouest, Plateforme In Vivo, 44000 Nantes, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Marionneau-Lambot
authors.affiliation: Cancéropôle du Grand Ouest, Plateforme In Vivo, 44000 Nantes, France.
authors.forename: Thibauld
authors.initials: T
authors.lastname: Oullier
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.|CHRU de Tours, 2 Boulevard Tonnellé, 37000 Tours, France.
authors.forename: Roseline
authors.initials: R
authors.lastname: Guibon
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.|CHRU de Tours, 2 Boulevard Tonnellé, 37000 Tours, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Fromont
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gutierrez-Pajares
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Domingo
authors.affiliation: CHRU de Tours, 2 Boulevard Tonnellé, 37000 Tours, France.|Inserm, U966, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Piver
authors.affiliation: Inserm, U966, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Moreau
authors.affiliation: Laboratoire de Biologie Cellulaire-Microscopie Electronique, Faculté de Médecine, Université François-Rabelais de Tours, 2 Boulevard Tonnellé, 37000 Tours, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Burlaud-Gaillard
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
authors.forename: Philippe G
authors.identifier: 0000-0003-4857-5279
authors.initials: PG
authors.lastname: Frank
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.|UFR Sciences Pharmaceutiques, Université François-Rabelais de Tours, 31 Avenue Monge, 37200 Tours, France.
authors.forename: Stéphan
authors.initials: S
authors.lastname: Chevalier
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.|UFR Sciences Pharmaceutiques, Université François-Rabelais de Tours, 31 Avenue Monge, 37200 Tours, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Besson
authors.affiliation: Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.|UFR Sciences et Techniques, Département de Physiologie Animale, Université François-Rabelais de Tours, Parc de Grandmont, 37200 Tours, France.|Institut Universitaire de France, 1, Rue Descartes, 75231 Paris Cedex 05, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Roger
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D021122:Protein Subunits / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D062585:Voltage-Gated Sodium Channel beta-4 Subunit / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D021122:Protein Subunits; C477263:SCN4B protein, human; D015222:Sodium Channels; D062585:Voltage-Gated Sodium Channel beta-4 Subunit; D020742:rhoA GTP-Binding Protein