Triple-Negative Breast Cancer Progression and Drug Resistance in the Context of Epithelial–Mesenchymal Transition.

Simple Summary: Triple-negative breast cancer (TNBC) is a challenging-to-treat breast cancer subtype, characterized by high recurrence, increased risk of metastasis, and lower survival for patients compared to other breast cancer subtypes. Depending on the clinical advancement of the disease, surgery, radiotherapy, and chemotherapy remain the standard treatment, though they often have limited long-term efficacy. Chemoresistance in TNBC is closely related to the epithelial–mesenchymal transition (EMT), a process where tumor cells gain mesenchymal-like characteristics. This, in turn, increases their metastatic potential and resistance to standard chemotherapeutic treatments. There is a growing interest in small-molecule inhibitors targeting EMT as a potential strategy to overcome resistance and improve TNBC patient outcomes. This review discusses the TNBC progression and drug resistance within the context of EMT, highlighting molecular features, key EMT protein markers, and signaling pathways. It also explores other mechanisms and factors related to chemoresistance in TNBC with an emphasis on treatment advancements. Triple-negative breast cancer (TNBC) is one of the most difficult subtypes of breast cancer to treat due to its distinct clinical and molecular characteristics. Patients with TNBC face a high recurrence rate, an increased risk of metastasis, and lower overall survival compared to other breast cancer subtypes. Despite advancements in targeted therapies, traditional chemotherapy (primarily using platinum compounds and taxanes) continues to be the standard treatment for TNBC, often with limited long-term efficacy. TNBC tumors are heterogeneous, displaying a diverse mutation profile and considerable chromosomal instability, which complicates therapeutic interventions. The development of chemoresistance in TNBC is frequently associated with the process of epithelial–mesenchymal transition (EMT), during which epithelial tumor cells acquire a mesenchymal-like phenotype. This shift enhances metastatic potential, while simultaneously reducing the effectiveness of standard chemotherapeutics. It has also been suggested that EMT plays a central role in the development of cancer stem cells. Hence, there is growing interest in exploring small-molecule inhibitors that target the EMT process as a future strategy for overcoming resistance and improving outcomes for patients with TNBC. This review focuses on the progression and drug resistance of TNBC with an emphasis on the role of EMT in these processes. We present TNBC-specific and EMT-related molecular features, key EMT protein markers, and various signaling pathways involved. We also discuss other important mechanisms and factors related to chemoresistance in TNBC within the context of EMT, highlighting treatment advancements to improve patients' outcomes. [ABSTRACT FROM AUTHOR]