Abstract 1452: Hypoxia-induced MIG-6 promotes glucose metabolic reprogramming and tumorigenesis in triple-negative breast cancer

Abstract

Abstract Treatment of triple-negative breast cancer (TNBC) remains challenging due to a lack of effective targeted therapies. Dysregulated glucose uptake and metabolism are essential for TNBC growth. Identifying the molecular drivers and mechanisms underlying the metabolic vulnerability of TNBC is the key to exploiting dysregulated cancer metabolism for therapeutic applications. Mitogen-inducible gene-6 (MIG-6) has long been thought as a feedback inhibitor that targets activated EGFR and suppresses the growth of tumors driven by constitutive activated mutant EGFR. Here, our bioinformatics and histological analyses uncovered that MIG-6 is upregulated in TNBC and that MIG-6 upregulation is positively correlated with poorer clinical outcomes in TNBC. Metabolic arrays and functional assays revealed that MIG-6 drives glucose metabolism reprogramming toward glycolysis. We found that hypoxia-induced MIG-6 promotes HIF1α protein stabilization and the subsequent upregulation of GLUT1 and other HIF1α-regulated glycolytic genes, substantiating the comprehensive regulation of MIG-6 in glucose metabolism. Moreover, our animal studies demonstrated that MIG-6 regulates GLUT1 expression in tumors and subsequent tumor growth in vivo. Collectively, this work reveals that MIG-6 is a novel prognosis biomarker, metabolism regulator, and molecular driver of TNBC. Citation Format: Jiabei He, Chien-Feng Li, Hong-Jen Lee, Dong-Hui Shin, Bruno De Carvalho, Chia-Hsin Chan. Hypoxia-induced MIG-6 promotes glucose metabolic reprogramming and tumorigenesis in triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1452.