Breast cancer stem cells: drivers of progression and therapeutic resistance

Abstract

Despite great progress in breast cancer management, metastasis, recurrence and therapeutic resistance remain major barriers to durable clinical benefit. Breast cancer stem cells (BCSCs) are now recognized as dynamic and plastic stem-like states rather than a fixed rare cell subset, shaped by epithelial–mesenchymal plasticity, hypoxia, therapeutic stress and tumor microenvironment (TME). Hybrid epithelial–mesenchymal phenotypes enable BCSCs to invade, disseminate, enter dormancy, evade immunity and form residual lesions that cause relapse. BCSCs drive resistance to chemo-, radio-, immuno-, HER2-targeted and endocrine therapies through drug efflux, antioxidant defense, DNA repair, metabolic reprogramming and alternative survival signals. Stromal and immune cells further sustain BCSC traits via cytokine crosstalk. This review summarizes the plastic features of BCSCs, their roles in metastasis and multidrug resistance, microenvironmental regulation and relevant therapeutic targeting strategies. Recent antigen-and biomarker-guided clinical trials indicate progress toward subtype-specific combination approaches, although their clinical efficacy remains to be established.