Ion-Channel Modulation in Breast Cancer: Mechanistic Convergence, Drug Repurposing, and Translational Priorities

Breast cancer is a molecularly heterogeneous disease in which therapeutic resistance and metastatic relapse continue to limit the benefits of endocrine, (human epidermal growth factor receptor 2) HER2-targeted, immune, and cytotoxic therapies. Accumulating evidence indicates that breast cancer cells co-opt voltage-gated sodium and calcium channels, diverse potassium channel subfamilies, hyperpolarization-activated cyclic nucleotide-gated channels (HCN), transient receptor potential (TRP) channels, chloride channels, purinergic receptors, and mechanosensitive channels to regulate membrane potential, proliferation, invasion, metastatic competence, immune suppression, and treatment resistance. Although these proteins originate from distinct gene families, their oncogenic outputs converge on a restricted set of signaling nodes, including epithelial-to-mesenchymal transition programs, pH-dependent matrix remodeling, PI3K/AKT/mTOR signaling, Ca2+-ROS homeostasis, autophagy, and regulated cell death pathways. This convergence creates opportunities to repurpose clinically used cardiovascular, neurological, anesthetic, and anti-infective drugs. The strongest current candidates include ranolazine and phenytoin for Nav1.5, ivabradine for HCN2/3, perioperative lidocaine, and the historically investigated chemosensitizer verapamil. However, target engagement, clinically achievable exposure, molecular subtype dependence, and on-target cardiac or neurological toxicity remain significant constraints. This review integrates channel biology with drug repurposing evidence, distinguishes approved drugs from experimental pharmacological probes, introduces a tiered framework based on mechanistic validation and translational readiness, and identifies subtype-stratified organoid and patient-derived xenograft testing as key steps toward precision oncology.