Core genes drive treatment resistance in triple-negative breast cancer: characteristics, mechanisms, intervention strategies.

Triple-negative breast cancer (TNBC) is highly malignant and exhibits significant heterogeneity. It readily develops resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. This review summarizes the primary resistance genes associated with treatment failure in TNBC, along with their fundamental characteristics and mechanisms of action. Most genes are overexpressed in TNBC and mediate cancer cell proliferation, survival, and drug resistance by regulating DNA damage repair, tumor stem cell properties, microtubule stability, and the abnormal activation of pathways. Focusing on key drug resistance genes such as PSENs, ATM, PIK3CA, and CDK4/6, we discovered that they promote tumor growth and metastasis by abnormally activating the Notch, Wnt/β-catenin, and PI3K/Akt/mTOR pathways. In response, targeted intervention strategies for drug-resistant genes have been proposed, including small-molecule inhibitors such as γ-secretase inhibitors and dual mTOR/PI3K inhibitors, as well as combination therapies involving Akt inhibitors and PD-1/PD-L1 inhibitors. They can suppress the expression of relevant genes, block drug resistance pathways, and restore drug sensitivity, providing a viable pathway and theoretical basis for TNBC treatment.