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Aerobic Glycolysis: A Novel Signature of Premalignancy in Disease-free Breast Tissue

  • Author(s): Benton, Geoffrey Marsing
  • Advisor(s): Tlsty, Thea D
  • et al.

It is well established that tumors exhibit abnormal aerobic glycolysis, a metabolic alteration known as "Warburg effect". However, it is unclear whether this phenotype reflects a metabolic shift during carcinogenesis or alternatively is a pre-existing event. In the present dissertation, we establish that a variant subpopulation of primary, non-transformed human mammary epithelial cells (vHMEC) shares this aerobic glycolysis signature with cancer cell lines. This phenotype is characterized by an increase in lactate production and synthesis as a result of lactate dehydrogenase (LDH) upregulation and is modulated by both hypoxia-induced factor HIF-1α and AKT. Strikingly, simultaneous over-expression of COX-2 and LDHA can be detected in morphologically normal epithelial cells in disease-free breast tissue, supporting that aerobic glycolysis pre-exists in vivo prior to carcinogenesis. Furthermore, we demonstrate that the lactate accumulation occurring in vHMEC can be readily detected by magnetic resonance spectroscopy (MRS), suggesting that aerobic glycolysis can be monitored in vivo. These novel findings further our understanding of pre-malignant events and could potentially lead to dramatic improvements in non-invasive detection of premalignant lesions in breast cancer patients.

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