Breast cancer (BC) progression is characterized by silencing of differentiation-specific genes and activation of genes promoting a switch from oxidative phosphorylation to aerobic glycolysis - the Warburg effect. Although the RUNX2 transcription factor promotes BC metastasis to bone, the mechanisms through which it regulates oncogenesis are not clear. We find that RUNX2 induction in MCF7 cells is associated with reduction in differentiation-specific estrogen receptor-α (ERα), increased expression of several glycolytic genes, increased glucose uptake (GLUT1), sensitivity to glucose starvation, and resistance to mitochondrial oxidative phosphorylation (OXPHOS) inhibitors. Conversely, endogenous RUNX2 knockdown in Hs578t triple-negative BC cells reduced cellular glucose addiction and expression of several glycolytic genes. Interestingly, these cells maintained high levels of PDHA1, which promotes OXPHOS by converting pyruvate to acetyl CoA to enter TCA cycle. In addition, RUNX2 knockdown resulted in a significant increase in oxygen consumption rate (OCR), indicative of enhanced mitochondrial OXPHOS. Mechanistically, the NAD-dependent histone deacetylase SIRT6, a known tumor suppressor, was a critical regulator of the RUNX2-mediated metabolic switch. SIRT6 levels were reduced in malignant BC tissues or cell lines that expressed high levels of RUNX2. This repression was regulated at both the transcriptional and post-translational levels and may account for the glycolytic phenotype and reduced mitochondrial OXPHOS in RUNX2 positive BC cells. Moreover, the expression of pyruvate dehydrogenase kinase 1 (PDHK1), which phosphorylates and inactivates PDH, was significantly higher in RUNX2 positive cells relative to RUNX2 negative cells. This reduction of PDHK1 was also observed in SIRT6 overexpressing cells, which suggests a potential role for SIRT6 as a repressor of this oncogenic kinase. Finally, ectopic expression of SIRT6 in RUNX2 positive cells increased, while specific knockdown of SIRT6 in RUNX2 negative cells decreased, respiration. In summary, these results suggest that RUNX2-mediated repression of the SIRT6 tumor suppressor may be a key pathway that promotes the Warburg effect and BC tumor progression.