SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer
Emeline Bon
(1)
,
Virginie Driffort
(1)
,
Frédéric Gradek
(1)
,
Carlos Martinez-Caceres
(2)
,
Monique Anchelin
(3)
,
Pablo Pelegrin
(4)
,
Maria-Luisa Cayuela
(3)
,
Séverine Marionneau-Lambot
(5)
,
Thibauld Oullier
(5)
,
Roseline Guibon
(6)
,
Gaëlle Fromont
(1)
,
Jorge Gutierrez-Pajares
(1)
,
Isabelle Domingo
(1)
,
Eric Piver
(7, 8)
,
Alain Moreau
(8)
,
Julien Burlaud-Gaillard
(9)
,
Philippe Frank
(1)
,
Stephan Chevalier
(1)
,
Pierre Besson
(1, 10)
,
Sébastien Roger
(1, 10)
1
N2C -
Nutrition, croissance et cancer (U 1069)
2 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
3 Hospital Clínico Universitario Virgen de la Arrixaca = University Hospital Virgen de la Arrixaca [Murcia]
4 Universidad de Murcia
5 Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire]
6 UFR de Médecine - EA4245 - Cellules Dendritiques, Immunomodulation et Greffes [Tours]
7 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
8 MAVIVH - U1259 Inserm - CHRU Tours - Morphogénèse et antigénicité du VIH et du virus des Hépatites
9 Laboratoire Biologie Cellulaire et Microscopie Electronique, Faculté Médecine
10 T2i - EA4245 - Transplantation, Immunologie, Inflammation [Tours]
2 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
3 Hospital Clínico Universitario Virgen de la Arrixaca = University Hospital Virgen de la Arrixaca [Murcia]
4 Universidad de Murcia
5 Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire]
6 UFR de Médecine - EA4245 - Cellules Dendritiques, Immunomodulation et Greffes [Tours]
7 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
8 MAVIVH - U1259 Inserm - CHRU Tours - Morphogénèse et antigénicité du VIH et du virus des Hépatites
9 Laboratoire Biologie Cellulaire et Microscopie Electronique, Faculté Médecine
10 T2i - EA4245 - Transplantation, Immunologie, Inflammation [Tours]
Pablo Pelegrin
- Function : Author
- PersonId : 791906
- ORCID : 0000-0002-9688-1804
- IdRef : 194286657
Thibauld Oullier
- Function : Author
- PersonId : 746831
- IdHAL : vincent-paille
- ORCID : 0000-0003-0424-0821
- IdRef : 099118270
Gaëlle Fromont
- Function : Author
- PersonId : 761945
- ORCID : 0000-0002-7730-2264
Alain Moreau
- Function : Author
- PersonId : 807816
- ORCID : 0000-0002-4827-9472
Philippe Frank
- Function : Author
- PersonId : 13191
- IdHAL : philippe-frank
- ORCID : 0000-0003-4857-5279
- IdRef : 092113419
Pierre Besson
- Function : Author
- PersonId : 13075
- IdHAL : pierre-besson
- ORCID : 0000-0003-1257-8005
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 NaV and 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.