Calcium dysregulation in breast cancer progression: mechanisms of calcicoptosis and therapeutic implications.

Disruption of calcium ion (Ca2+) homeostasis represents a critical mechanism in breast cancer (BC) progression, with aberrant Ca2+ transport through store-operated Ca2+ entry pathways, plasma membrane channels, and membrane contact sites (MCSs) playing a significant role in malignant transformation, metastasis, and therapeutic resistance. This dysregulation involves complex interactions among endoplasmic reticulum Ca2+ storage systems, Ca2+-dependent signaling cascades, and specialized MCSs that facilitate abnormal Ca2+ transfer between cellular organelles. Of particular therapeutic relevance, calcicoptosis-a novel form of Ca2+ overload-induced cell death-exhibits remarkable selectivity for BC cells over normal tissues, offering promising avenues for therapy, particularly in aggressive subtypes with limited treatment options. The distinct Ca2+ handling properties of BC cells present opportunities for targeted interventions that exploit these vulnerabilities through pharmacological modulation of Ca2+ transport mechanisms. This review synthesizes current understanding of Ca2+-mediated pathways in BC and outlines a framework for developing precision medicine approaches that leverage Ca2+ dysregulation as both a biomarker and a therapeutic target, with the potential to transform treatment strategies for patients with treatment-resistant disease.