Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.

// Michaela Nelson 1 , Ming Yang 1 , Rebecca Millican-Slater 2 , William J. Brackenbury 1 1 Department of Biology, University of York, Heslington, York, YO10 5DD, UK 2 Department of Histopathology, St James’s University Hospital, Leeds, LS9 7TF, UK Correspondence to: William J. Brackenbury, e-mail: william.brackenbury@york.ac.uk Keywords: adhesion, breast cancer, invasion, metastasis, voltage-gated Na + channel Received: May 22, 2015      Accepted: September 25, 2015      Published: October 06, 2015 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 Na v 1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Na v 1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Na v 1.5 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 Na v 1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Na v 1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro , Na v 1.5 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 Na v 1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Na v 1.5 may be useful for reducing metastasis.