The Underlying Mechanisms and Emerging Strategies to Overcome Resistance in Breast Cancer
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Breast cancer (BC) remains a leading cause of cancer related mortality among women worldwide. Despite significant advances in early detection and targeted therapies, treatment of resistant cancers continues to be a major hindrance in long term patient outcomes. Therefore, a comprehensive understanding of the underlying mechanisms and strategies to overcome resistance in BC is urgently needed. Resistance is likely driven by diverse processes such as drug efflux transporter upregulation; genetic mutations and signaling rewiring (e.g., ESR1, PIK3CA/PTEN, PI3K/Akt/mTOR); cancer stem cells and exosome RNA transfer; modulation of tumor microenvironment; epigenetic and metabolic reprogramming; and immune evasion—all of which compromise treatment efficacy. As tumors evolve, monotherapies rapidly lose effectiveness, and metastatic progression further worsens outcomes. In this review, we systematically examine the key metabolic, genetic, epigenetic, immunological, and microenvironmental drivers of BC resistance and emerging strategies to treatments. Further, we also explore the role that artificial intelligence (AI) can play in enhancing early detection, clinical-decision making, developing targeted therapies, and designing vaccines, which can aid in overcoming resistance. By integrating mechanistic insights with cutting-edge technologies, our review highlights the potential of next-generation interventions to overcome resistance and improve patient prognosis and outcome.