Characterizing the role of pyruvate dehydrogenase in breast cancer etiology
The central premise of the PI’s research is to investigate the cancer’s glucose dependence, known as the Warburg effect, as novel treatment target against breast cancer. The current proposal aims to investigate the effect of PDH on the development of cancer and its contribution to establishing several hallmarks of cancer namely growth factor independent growth, evasion of apoptosis and ability to invade.
Breast cancer is the most diagnosed and second leading cause of cancer death in the United States. The Agency for Healthcare research and Quality (AHRQ) estimates that the direct medical costs for all cancers in the US in 2011 were $88.7 billion. While mortality rates have declined, overall survival largely depends on early stage detection, and current therapies vary in effectiveness and are often extremely high cost. This proposal explores manipulation of the metabolic needs of cancer cells as a potentially novel, lower cost, adjunctive approach to cancer therapy. Virtually all tumors have increased metabolic need for glucose due to forgoing complete oxidation of glucose in favor of fermenting glucose to lactate even in the presence of sufficient oxygen levels, a paradox known as the Warburg effect. This aerobic glycolysis cancer phenotype is already exploited in PET imaging using labeled 18F-fluorodeoxyglucose. Limited case studies indicate that glucose deprivation through application of a ketogenic diet slowed disease progression or even caused remission, supported by similar results in mouse model, but systematic analysis of aerobic glycolysis acquisition and its impact on the cancer phenotype is lacking. Since aerobic glycolysis exists in virtually all cancers, it is prudent to assume that development of the aerobic phenotype occurs early in carcinogenesis and may therefore be a critical determinant for a dysplastic or metaplastic lesion to progress in its transformation towards cancer development. Analysis of metabolic pathways points to oxidative pyruvate decarboxylation as the crucial step in continuing glucose oxidation rather than remaining in the oxygen independent metabolic reactions of the glycolytic pathway. The mitochondrial membrane Pyruvate Decarboxylase Complex (PDC) performs the necessary steps (transport into mitochondrial matrix, conversion to acetyl-CoA and NADH production) for pyruvate to enter the TCA cycle. The rate-limiting step in this complex is the enzyme pyruvate dehydrogenase (PDH), making it a prime target for investigation of the aerobic glycolysis phenotype observed in cancer cells.