Topoisomerase Inhibitor Resistance in Breast Cancer: Exploring Alterations in Cellular Metabolism and Properties Driving Drug Insensitivity

Topoisomerase (Topo) inhibitors remain a cornerstone in the treatment of advanced breast cancer (BC), despite challenges such as dose-limiting toxicities and the emergence of drug resistance.The effective development of novel therapies targeting aggressive and metastatic BC, particularly those characterized by dynamic heterogeneity and therapeutic refractoriness, requires a comprehensive understanding of the underlying resistance mechanisms.These mechanisms span intrinsic and extrinsic factors, including impaired drug delivery, dysregulated signaling pathways, phenotypic plasticity, tumor microenvironmental influences, and genetic and epigenetic alterations.This review explores the cellular adaptations and metabolic reprogramming that contribute to reduced sensitivity to Topo inhibitors in BC.Furthermore, it highlights recent advances in repurposing Topo inhibitors as promising therapeutic candidates, offering new opportunities to overcome resistance and improve clinical outcomes in breast cancer management.