Decoding the key hallmarks of chemoresistance: A proteomic tale from breast cancer research

Chemoresistance denotes the intricate, multifactorial molecular mechanisms by which malignant cells subvert the cytotoxicity of chemotherapeutic agents, thereby impeding therapeutic efficacy. This phenomenon is orchestrated through a confluence of processes, which we propose as the major hallmarks of chemoresistance in cancer. Dysregulation of drug transporters, activation of pro-survival pathways, cancer stem cell driven proliferation, DNA damage and repair mechanisms, evasion of apoptosis, autophagy induction, secretion of extracellular vesicles, and metabolic reprogramming represents the major mechanisms of chemoresistance in cancer. Breast cancer is one of the most common and aggressive types of cancer, with significant challenges in treatment due to its heterogeneity. Despite progress in various treatment regimens, chemoresistance continues to be a significant challenge in the effective management of breast cancer. In this context, high-throughput proteomic methodologies, which quantitatively assess proteome-wide alterations and explore post-translational modifications, can provide an unbiased framework for unraveling the molecular intricacies of chemotherapy resistance. This article comprehensively reviews the application of advanced proteomic techniques in elucidating the pathophysiological mechanisms of chemoresistance in breast carcer. Additionally, it highlights promising protein signatures uncovered via proteomic tools, as well as therapeutic strategies targeting chemoresistant hallmarks to overcome drug resistance in breast cancer. By leveraging the mightiness of proteomic technologies, we move closer to efficient, potent and personalized therapeutic interventions for chemoresistant breast cancer.