Metabolic heterogeneity in TNBCs: A potential determinant of therapeutic efficacy of 2-deoxyglucose and metformin combinatory therapy

Breast cancers (BCs) remain the leading cause of cancer-related deaths among women worldwide. Among the different types of BCs, treating the highly aggressive, invasive, and metastatic triple-negative BCs (TNBCs) that do not respond to hormonal/human epidermal growth factor receptor 2 (HER2) targeted interventions since they lack ER/PR/HER2 receptors remains challenging. While almost all BCs depend on glucose metabolism for their proliferation and survival, studies indicate that TNBCs are highly dependent on glucose metabolism compared to non-TNBC malignancies. Hence, limiting/inhibiting glucose metabolism in TNBCs should curb cell proliferation and tumor growth. Previous reports, including ours, have shown the efficacy of metformin, the most widely prescribed antidiabetic drug, in reducing cell proliferation and growth in MDA-MB-231 and MDA-MB-468 TNBC cells. In the current study, we investigated and compared the anticancer effects of either metformin (2 mM) in glucose-starved or 2-deoxyglucose (10 mM; glycolytic inhibitor; 2DG) exposed MDA-MB-231 and MDA-MB-468 TNBC cells. Assays for cell proliferation, rate of glycolysis, cell viability, and cell-cycle analysis were performed. The status of proteins of the mTOR pathway was assessed by Western blot analysis. Metformin treatment in glucose-starved and 2DG (10 mM) exposed TNBC cells inhibited the mTOR pathway compared to non-treated glucose-starved cells or 2DG/metformin alone treated controls. Cell proliferation is also significantly reduced under these combination treatment conditions. The results indicate that combining a glycolytic inhibitor and metformin could prove an efficient therapeutic approach for treating TNBCs, albeit the efficacy of the combination treatment may depend on metabolic heterogeneity across various subtypes of TNBCs.