title: Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.
abstract: Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis.
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Nelson
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Histopathology, St James's University Hospital, Leeds, LS9 7TF, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Millican-Slater
authors.affiliation: Department of Biology, University of York, Heslington, York, YO10 5DD, UK.
authors.forename: William J
authors.initials: WJ
authors.lastname: Brackenbury
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D009362:Neoplasm Metastasis
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
keywords: adhesion; breast cancer; invasion; metastasis; voltage-gated Na+ channel