Abstract 3076: Unveiling the therapeutic potential of β-catenin inhibition in triple negative breast cancers: Targeting the Warburg effect

Abstract

Abstract Introduction: Triple Negative Breast Cancer (TNBC) exhibits increased glycolysis, known as the Warburg effect. Recent research, including our own Nanostring nCounter studies, identify β-catenin as an oncoprotein linked to elevated glycolysis in TNBC tumors. Our current research explores the impact of β-catenin inhibitors on glycolysis in TNBC cell lines and an in vivo CDX model. Method: We employed immunohistochemistry to assess 98 TNBCs for the presence of β-catenin, PFKP, LDH-A, and MCT1 proteins, exploring their correlation with clinicopathological factors. In in-vitro experiments using MDA-MB-231, MDA-MB-468, and 4T1 cell lines, we investigated how β-catenin inhibitors (XAV939 & Axitinib) affected aerobic glycolysis components, and TNBC cell characteristics (proliferation, migration, invasion, and stemness). For in-vivo validation, 4T1 TNBC xenografts were employed to confirm our findings. Results: Among the 98 TNBC patients, 63 (64%) displayed cytoplasmic/or nuclear β-catenin staining. Additionally, cytoplasmic accumulation of PFKP was observed in 52/98 (53%), increased cytoplasmic LDH-A expression in 57/98 (58%), and membranous MCT-1 expression in 50/98 (51%) TNBC patients. Notably, significant positive correlations were found between nuclear/cytoplasmic β-catenin and cytoplasmic PFKP (p = 0.001) as well as membranous MCT1 (p = 0.014). Furthermore, β-catenin, PFKP, LDHA, and MCT1 proteins were overexpressed in all TNBC cell lines thereby supporting their glycolytic nature. Comparative analyses between XAV939 and Axitinib revealed that Axitinib significantly reduced various TNBC cell parameters, including migration, invasion, lactate production, colony-forming ability, and expression of aerobic glycolytic pathway proteins. In the in-vivo studies, 30mg/kg Axitinib in a female Balb/c-4T1 xenograft model resulted in a substantial reduction in tumor volume and weight. Conclusion: Our findings show that increased levels of β-catenin play an important role in regulating aerobic glycolysis in TNBCs. Furthermore, our findings also highlight Axitinib's potential as an effective therapeutic agent for the treatment of β-catenin-positive TNBCs. Citation Format: Sheikh Mohammad Umar, Shruti kahol, Arundhathi Dev JR, Akanksha Kashyap, Sandeep R. Mathur, Ajay Gogia, S.V.S Deo, Chandra Prasad. Unveiling the therapeutic potential of β-catenin inhibition in triple negative breast cancers: Targeting the Warburg effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3076.