Since the 1970s, cancer incidence in the UK has steadily increased and although survival rates continue to improve, cancer is responsible for more than one in four deaths. Metastasis, the spreading of cancer cells from primary sites to form secondary tumours in distant organs, is a major cause of physical and psychological morbidity, and is the leading cause of cancer-related deaths. Metastasis is estimated to be responsible for around 90% of deaths from solid tumours. Treatment options for patients with metastatic disease are largely limited to palliation. Thus, there is an urgent unmet need to identify new molecular targets and cost-effective adjuvant therapies with curative intent.Voltage-gated Na+ channels (VGSCs) are heteromeric proteins composed of pore-forming α subunits and smaller β subunits. The β subunits are multifunctional channel modulators and are members of the immunoglobulin superfamily of cell adhesion molecules. VGSC α and β subunits are best characterised in the central nervous system (CNS), where they play a critical role in regulating electrical excitability, neurite outgrowth, fasciculation, pathfinding and migration during development (Brackenbury & Isom, 2011). VGSCs are also present in metastatic cells from a number of cancers (Brackenbury, 2012). In particular, expression of α subunits has been shown to favour an invasive/metastatic phenotype. For example, Nav1.5 (encoded by SCN5A) is expressed in metastatic breast cancer cells, and potentiates their invasion and migration (Fraser et al., 2005). Using the Oncomine expression array database of clinical cancer specimens, we have found that SCN5A is up-regulated in breast cancer and associates with disease recurrence, metastasis and reduced survival. The VGSC-blocking anticonvulsant phenytoin inhibits Na+ current in metastatic breast cancer cells, particularly at depolarised holding voltages. It may thus be an effective VGSC blocker in cancer cells, which typically have depolarised membrane potentials (Yang & Brackenbury, 2013). At a concentration within the therapeutic range used to treat epilepsy, phenytoin inhibits migration and invasion of breast cancer cells in vitro, suggesting that pharmacological targeting of Na+ current may have therapeutic utility (Yang et al., 2012).β subunits are also expressed in tumour cells. For example, β1 (encoded by SCN1B) is expressed in breast cancer cells, where it functions as a cell adhesion molecule (Chioni et al., 2009). SCN1B mRNA and β1 protein are up-regulated in clinical breast cancer specimens, compared with normal tissue. Further, β1 up-regulation substantially increases tumour growth and metastasis in an orthotopic xenograft mouse model of breast cancer. β1 over-expression also increases vascularisation and reduces apoptosis in the primary tumours, and β1-expressing tumour cells have an elongate mesenchymal-like morphology. β1 potentiates outgrowth of elongated processes from breast cancer cells co-cultured with fibroblasts, via trans-homophilic adhesion. β1-mediated process outgrowth in breast cancer cells requires both Na+ current and the presence and activity of fyn kinase, thus replicating the mechanism by which β1 regulates neurite outgrowth in CNS neurons. We conclude that when present in breast tumours, β1 enhances pathological growth and cellular dissemination by recapitulating its well-defined role in CNS ontogeny. This is the first demonstration of a functional role for β1 in cancer in vivo. Moreover, β1 expression in breast cancer supports the notion that carcinomas can acquire neuronal-like characteristics in order to progress.Together, our data support the hypothesis that VGSC α and β subunits are up-regulated in breast cancer, favouring an invasive/metastatic phenotype, and may thus be promising targets for therapeutic intervention. We propose that repurposing existing VGSC-blocking drugs (e.g. antiepileptics, antiarrhythmics) may have the potential to improve patient outcomes in the metastatic setting. In particular, phenytoin, a clinically approved oral anticonvulsant, should be further studied as a potentially cost-effective treatment. In addition, targeting β1-mediated adhesion interactions may have potential as a novel anti-cancer therapy.