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. 2025 Sep;477(9):1191-1200.
doi: 10.1007/s00424-025-03106-3. Epub 2025 Jul 24.

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

Paula Rhana  1 , Flávia Carvalho Aguiar  2 , Diego Santos Souza  3 , Ênio Ferreira Lima  2 , Andréia Laura Prates Rodrigues  3 , Jader Santos Cruz  4
Affiliations

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

Paula Rhana et al. Pflugers Arch. 2025 Sep.

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.

Keywords: Breast cancer; Ion channels; Tumor aggressiveness; Voltage-gated sodium channels.

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Conflict of interest statement

Declarations. Ethical approval and consent to participate: Not applicable. Human Ethics: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Clinical trial number: Not applicable. Conflict of interest: The authors declare that there is no conflict of interest.

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