β-Catenin–Facilitated Glycolytic Reprogramming Fuels TNBC Progression - Therapeutic Blockade with XAV939 - Technology in Cancer Research & Treatment

Sep 22, 2026

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Glycolytic phenotype supports migration and metastasis in triple negative breast cancers (TNBCs), making the molecular basis of increased aerobic glycolysis critical for identifying progression drivers. Analyzing β-catenin together with glycolytic proteins (PFKP, LDHA, MCT1) in TNBC patients (n=98) links combined expression to poorer survival. In TNBC models, the β-catenin inhibitor XAV939 suppresses β-catenin-driven aerobic glycolysis, reduces glycolytic activity, and impairs proliferation, migration, invasion, and clonogenicity, supporting therapeutic potential.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

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Abstract

Introduction

Methods

Results

Conclusion

Keywords

Received, revised, accepted

β-Catenin–Facilitated Glycolytic Reprogramming Fuels TNBC Progression: Therapeutic Blockade with XAV939 Technology in Cancer Research & Treatment Volume 25: 1-14 © The Author(s) 2026 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions)[ ](sagepub.com/journals-permissions)[DOI: 10.1177/15330338261425407](DOI: 10.1177/15330338261425407)[ ](DOI: 10.1177/15330338261425407)[journals.sagepub.com/home/tct](journals.sagepub.com/home/tct) Sheikh Mohammad Umar, MSc 1, Shruti Kahol, PhD2, Sandeep R. Mathur, MD2, Ajay Gogia, DM3, S.V.S. Deo, MS4, Shivam Pandey, PhD5, and Chandra Prakash Prasad, PhD 1 Abstract Introduction: Glycolytic 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. Methods: β-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. In vitro, 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. Results: β-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. In vitro, 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). Conclusion: Overall, 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. Keywords triple negative breast cancer, aerobic glycolysis, β-catenin, XAV939, migration Received: October 30, 2025; revised: January 10, 2026; accepted: January 29, 2026 Introduction Triple-negative breast cancers (TNBCs) subtype is distinguished by their aggressive nature, inadequate treatment options, high recurrence rate, and inferior prognosis.1 Like inﬂammatory or metaplastic subtypes, TNBC is also challenging to treat and often demands more intensive approaches. In the absence of precision therapy, the therapeutic management ofTNBC primarily depends on a multimodal approach that includes chemotherapy, radiation therapy, and surgery. Although initial response rates to adjuvant therapy are satisfactory, TNBC patients frequently demonstrate disease recurrence and early metastatic onset, highlighting the critical need to discover new targets for effective treatment.2,3 In recent studies, researchers have shown the metabolic dependence 1 Department of Medical Oncology (Lab), Dr BRA IRCH, AIIMS, Ansari Nagar, New Delhi, India 2Department of Pathology, AIIMS, Ansari Nagar, New Delhi, India 3Department of Medical Oncology, Dr BRA IRCH, AIIMS, Ansari Nagar, New Delhi, India 4Department of Surgical Oncology, Dr BRA IRCH, AIIMS, Ansari Nagar, New Delhi, India 5Department of Biostatistics, AIIMS, Ansari Nagar, New Delhi, India Corresponding Author: Chandra Prakash Prasad, PhD, Additional Professor, Room No. 411, Department of Medical Oncology (Lab), DR BRA IRCH, All India Institute of Medical Sciences, Ansari Nagar, New Delhi-110029, INDIA. Email: [researchchandra@gmail.com](researchchandra@gmail.com); [p

FAQs

What role does aerobic glycolysis play in TNBC progression?

Aerobic glycolysis supports cancer cell migration and metastasis, contributing to aggressive behavior and early recurrence in TNBC.

How were β-catenin and glycolytic proteins evaluated in TNBC patients?

β-catenin and glycolytic proteins (PFKP, LDHA, MCT1) were assessed by immunohistochemistry, and prognostic value was analyzed using Kaplan-Meier and Cox regression.

What effect does XAV939 have in TNBC models?

XAV939 inhibits β-catenin-driven aerobic glycolysis by downregulating β-catenin and glycolytic proteins, reducing glycolytic activity and impairing aggressive phenotypes such as proliferation, migration, invasion, and clonogenicity.

Sep 22, 2026

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