Voltage-gated Na+ channels: key players in the early tumorigenesis of breast cancer.

Abstract

Voltage-gated Na⁺ channels (VGSCs) are recognized for their roles in cancer biology, particularly in promoting tumor aggressiveness. However, their presence and functional significance in early-stage breast cancer remain poorly understood. This study investigates the physiological role of VGSCs in breast cancer progression, focusing on their contribution to metastatic potential and their promise as novel therapeutic targets. To address these issues, we examined VGSCs expression and electrophysiological properties in two primary breast tumor cell lines, MACL-1 and MGSO-3, using patch-clamp whole-cell recordings. Both exhibited fast inward currents, peaking near 0 mV, which were abolished by extracellular Na⁺ removal, confirming that inward current was due to the presence of VGSCs. Pharmacological inhibition with tetrodotoxin (TTX, 100 nM) showed that MACL-1 cells exclusively express TTX-sensitive VGSCs, while MGSO-3 cells express both TTX-sensitive and -resistant VGSCs. In contrast, non-tumoral MCF-10A breast cells, although they express VGSCs, showed no detectable inward Na⁺ current. Despite having similar Na⁺ current activation properties, the Na⁺ current in MGSO-3 cells exhibited slower inactivation kinetics compared to MACL-1 cells, suggesting functional heterogeneity. However, neither TTX nor anemone toxin (ATX) influenced proliferation or migration, challenging the established link between VGSCs and tumor aggressiveness in early-stage breast cancer. Immunocytochemistry revealed the presence of Nav1.5 (a TTX-resistant VGSC isoform), Nav1.6, and Nav1.7 (TTX-sensitive VGSCs isoforms) in both non-tumoral and tumoral cells, with these isoforms localized to different intracellular compartments, raising questions about their regulatory roles.