Abstract 6651: β-catenin-mediated aerobic glycolysis: a marker of poor prognosis in triple-negative breast cancer

Abstract Aerobic glycolysis has emerged as a crucial regulator of cancer cell migration and metastasis in various cancers including TNBCs. Characterization of molecular pathways associated with increased aerobic glycolysis in TNBCs could provide key mechanistic insights into the regulators of TNBC progression. Here, we demonstrated for the first time the theranostic potential of the β-catenin-PFKP-LDHA-MCT1 axis that drives aerobic glycolysis in TNBCs. β-catenin and related glycolytic proteins (PFKP, LDHA, and MCT1) were analyzed in triple-negative breast cancer (TNBC) patients (n=98) using immunohistochemistry (IHC). Prognostic significance was assessed through Kaplan-Meier survival analysis and Cox regression. Additionally, we compared the efficacy of two β-catenin inhibitors, XAV939 and Axitinib, in suppressing β-catenin-driven aerobic glycolysis in both in vitro and in vivo TNBC models. We showed that β-catenin and its associated glycolytic proteins (PFKP, LDHA, and MCT1) are overexpressed in more than 50% of TNBC cases. Kaplan-Meier survival analysis and Cox regression revealed that elevated β-catenin expression, combined with high levels of other glycolytic proteins (β-catenin+MCT1high; β-catenin+PFKP+MCT1high; β-catenin+LDHA+MCT1high; and β-catenin+PFKP+LDHA+MCT1high), was linked to poor prognosis, highlighting the role of β-catenin-regulated aerobic glycolysis in TNBC aggressiveness. Additionally, we found that Axitinib, compared to XAV939, more effectively reduced β-catenin and glycolytic protein expression, lactate production, cell migration, invasion, and colony formation in TNBC cell lines. In conclusion, this study is the first to identify a novel β-catenin-regulated aerobic glycolysis pathway in triple-negative breast cancer (TNBC). We also demonstrated that Axitinib is a more effective inhibitor of this pathway than XAV939. Citation Format: Chandra Prakash Prasad, Sheikh Mohammad Umar, Shruti Kahol, Sandeep R. Mathur. β-catenin-mediated aerobic glycolysis: a marker of poor prognosis in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6651.