A novel Na_v1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis

Solid tumours have abnormally high intracellular [Na⁺]. The activity of various Na⁺ channels may underlie this Na⁺ accumulation. Voltage-gated Na⁺ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Na_v1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Na_v1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Na_v1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na⁺/K⁺ ATPase, thus promoting H⁺ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na⁺ influx through Na_v1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na⁺ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Na_v1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.