β-Catenin–Facilitated Glycolytic Reprogramming Fuels TNBC Progression: Therapeutic Blockade with XAV939

IntroductionGlycolytic phenotype positively supports cancer cell migration and metastasis in various cancers including Triple negative breast cancers (TNBCs). In-depth understanding of molecular pathways associated with increased aerobic glycolysis in TNBCs could provide key insights into the drivers of TNBC progression.Methodsβ-catenin and glycolytic proteins (PFKP, LDHA, MCT1) were assessed by Immunohistochemistry (IHC) in TNBC patients (n = 98), with prognostic value evaluated by Kaplan-Meier and Cox regression. <i>In vitro</i>, the β-catenin inhibitor ie, XAV939 was tested for suppressing β-catenin-driven aerobic glycolysis in TNBC models using MTT for proliferation, Western blotting for protein expression, and wound healing, droplet invasion, and colony formation assays for physiological changes.Resultsβ-catenin and glycolytic markers (PFKP, LDHA, MCT1) were overexpressed in >50% of TNBCs. Kaplan-Meier and Cox regression analyses showed that combined expression of β-catenin with glycolytic markers correlated with reduced survival. <i>In vitro</i>, XAV939 suppressed β-catenin-driven aerobic glycolysis in TNBC cells, downregulating β-catenin and glycolytic proteins, reducing glycolytic activity, and impairing aggressive phenotypes (proliferation, migration, invasion, clonogenicity).ConclusionOverall, our results highlight the crucial role of β-catenin in controlling aerobic glycolysis via regulation of key glycolytic proteins, thereby positively driving the progression and metastasis of TNBCs. Additionally, our data strongly establish that XAV939 effectively inhibits glycolytic phenotype, thereby suggesting its therapeutic potential in TNBC patients.