Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

Oncogene. 2009 Oct 22;28(42):3689-701. doi: 10.1038/onc.2009.229. Epub 2009 Aug 10.


ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Deoxyglucose / pharmacology
  • Down-Regulation
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Glucose / metabolism
  • Glycolysis / drug effects
  • Glycolysis / genetics*
  • Heat Shock Transcription Factors
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism*
  • Lactate Dehydrogenase 5
  • Lactic Acid / biosynthesis
  • Oxamic Acid / pharmacology
  • Oxygen / metabolism
  • RNA, Small Interfering / genetics
  • Receptor, ErbB-2 / deficiency
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Up-Regulation*


  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Isoenzymes
  • RNA, Small Interfering
  • Transcription Factors
  • Lactic Acid
  • Deoxyglucose
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • Receptor, ErbB-2
  • Glucose
  • Oxamic Acid
  • Oxygen