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.