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

Abstract Solid tumours have abnormally high intracellular [Na + ]. The activity of various Na + transporting proteins including channels may underlie this Na + accumulation. Here, we show that voltage-gated Na + channels (VGSCs) are functionally active in a subset of breast cancer cell lines, cancer-associated fibroblasts, xenograft tumours and metastases. Downregulation of the Na v 1.5 VGSC in xenograft breast tumours suppresses expression of invasion-regulating genes, consistent with previous studies showing that Na v 1.5 promotes invasion in cancer cells. We also show that Na v 1.5 activity increases glycolysis, promoting extracellular acidification that would facilitate this invasion. In a reciprocal interaction, acidic extracellular pH elevates persistent Na + influx through Na v 1.5 in breast cancer cells. Using a mathematical model, we show that Na v 1.5 activity can sustain production of extracellular H + . We show that likely VGSC currents are detectable in patient-derived breast tumour cells and tissues. Furthermore, protein expression of Na v 1.5 strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. Together, these findings show positive feedback between extracellular acidification and movement of Na + into cancer cells which can facilitate invasion. They also highlight the clinical significance of Na v 1.5 as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.