PHB2 Promotes Glycolytic Reprogramming in Triple-Negative Breast Cancer Through FOXM1-Dependent Activation of LDHB.

Abstract

Triple-negative breast cancer (TNBC) presents significant clinical challenges due to its aggressive phenotype and the limited availability of molecularly targeted therapies. In this study, we investigated the therapeutic potential of targeting PHB2 in TNBC by combining bioinformatics analysis with comprehensive in vitro and in vivo experiments (CCK-8, colony formation and Transwell migration assays) to evaluate the clinical significance of PHB2 and its role in regulating the malignant phenotypes of TNBC cells. To dissect the underlying molecular circuitry, we measured glycolytic flux through glucose uptake and lactate production assays, mapped transcription-factor occupancy by chromatin immunoprecipitation (ChIP), and assessed promoter activity using dual-luciferase reporters. We demonstrate that elevated PHB2 expression leads to unfavorable prognosis in TNBC. Mechanistically, PHB2 drives glycolytic reprogramming by enhancing FOXM1-mediated transcriptional activation of LDHB, a key enzyme in anaerobic glycolysis. These findings highlight PHB2 as a critical regulator of metabolic adaptation and aggressiveness in TNBC, positioning it as a promising candidate for targeted therapy.