Unveiling the Role of Glutathione <i>S</i> -transferase Protein in Breast Cancer Drug Resistance: Insights into the Signaling Pathways and Therapeutic Implications

Breast cancer remains one of the most prevalent malignancies among women worldwide. Current therapeutic strategies comprising surgery, radiation therapy, immunotherapy, and postoperative chemotherapy have significantly improved patient outcomes. However, the emergence of multidrug resistance (MDR) continues to impede treatment efficacy. Several factors contribute to MDR, including drug inactivation, enhanced metabolism, transporter protein-mediated drug efflux, and epigenetic alterations. Among these, the overexpression of drug-metabolizing enzymes such as glutathione S-transferases (GSTs), alongside transporter proteins like the breast cancer resistance protein (BRCA), plays a pivotal role. Numerous studies have demonstrated that GSTs not only accumulate on the cell surface but also interact with proteins involved in critical signaling pathways, thereby enhancing mRNA translation, promoting cell proliferation, and inhibiting apoptosis. These interactions highlight an essential link between GST activity and breast cancer progression. To counter GST-mediated resistance, various GST inhibitors and prodrugs specifically targeting cancer cells with elevated GST expression have been developed, showing considerable therapeutic promise. Nevertheless, the precise molecular mechanisms underlying GST-induced drug resistance remain incompletely understood. A comprehensive understanding of these mechanisms is vital for the rational design of effective therapeutic interventions. Given that breast cancer continues to be the leading cause of cancer-related mortality in women, in-depth exploration of GST’s role in altering the tumor microenvironment (TME), regulating metastasis, and modulating apoptotic pathways is imperative. This review consolidates previous findings and integrates recent experimental evidence, providing a foundational framework for identifying novel GST-related targets in drug design and delivery.