Breast cancer is the most common malignancy among women worldwide and is closely associated with metabolic reprogramming during malignant progression. TIGAR (TP53-Induced Glycolysis and Apoptosis Regulator) is highly expressed in a substantial proportion of human breast cancers and has emerged as an important regulator of tumor metabolism. However, the molecular network through which TIGAR promotes breast cancer progression and its clinical translational potential remain incompletely understood. This review summarizes the molecular mechanisms underlying the oncogenic functions of TIGAR in breast cancer, including regulation of cell-cycle progression through the p21-CDK2 axis, activation of the c-Myc/HIF-1α positive-feedback loop and the STAT3-mediated immune-metabolic axis, suppression of ROS-dependent apoptosis and ferroptosis, and remodeling of oxidative phosphorylation and lipid metabolism. Clinically, high TIGAR mRNA expression has been associated with shorter progression-free survival in breast cancer (HR = 1.56, P = 1.9 × 10⁻⁸), and this association remained significant after multivariable adjustment in an analysis of publicly available breast cancer transcriptomic and clinical outcome datasets. However, the prognostic significance of TIGAR requires further validation in independent clinical cohorts. Preclinical studies further suggest that metabolic interventions targeting mitochondrial function, nanomedicine-based strategies, and modulation of cholesterol metabolism may counteract TIGAR-associated tumor-promoting effects. This review integrates current evidence on the molecular and metabolic functions of TIGAR in breast cancer and discusses the opportunities and challenges of targeting TIGAR as part of combination metabolic therapies.
Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expressions, with poor prognosis and limited treatment options. Studies have demonstrated the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy in patients with programmed death-ligand 1 (PD-L1)-positive advanced TNBC. Radiotherapy (RT) may enhance therapeutic effects when combined with ICIs. In this ongoing single-arm, multicenter phase II trial (IMRad-Br; jRCTs021210010), we aimed to evaluate the safety and feasibility of combining atezolizumab/nab-paclitaxel with local RT in patients with inoperable or recurrent PD-L1-positive TNBC. Patients received atezolizumab (840 mg on days 1 and 15 of a 28-day cycle) and nab-paclitaxel (100 mg/m2 on days 1, 8, and 15), followed by local RT at 30 Gy in five fractions. A safety run-in was conducted in six evaluable patients to assess protocol-defined prespecified adverse events of interest (PAEIs). Among the seven patients enrolled, one PAEI was observed (grade 4 liver injury), which improved with treatment interruption and follow-up. Two additional serious adverse events occurred but were unrelated to the study treatment. No unexpected toxicity was observed. Combination therapy was deemed feasible by an Independent Data Monitoring Committee. The combination of atezolizumab/nab-paclitaxel with local RT was feasible and did not result in unexpected toxicities during the safety run-in phase. This study is ongoing to evaluate the safety and therapeutic potential of ICI–RT combination therapy for recurrent PD-L1-positive TNBC. The final analysis will determine whether this approach merits broader clinical adoption.
