Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells

J Clin Invest. 2019 Mar 1;129(3):1030-1046. doi: 10.1172/JCI121685. Epub 2019 Jan 28.


Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress-induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.

Keywords: Breast cancer; Metabolism; Oncology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ascorbic Acid / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Epinephrine / metabolism*
  • Female
  • Humans
  • L-Lactate Dehydrogenase / metabolism*
  • MCF-7 Cells
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplastic Stem Cells / enzymology*
  • Neoplastic Stem Cells / pathology
  • Proto-Oncogene Proteins c-myc / metabolism
  • Snail Family Transcription Factors / metabolism
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism*
  • Stress, Psychological / pathology


  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • SNAI1 protein, human
  • Snail Family Transcription Factors
  • L-Lactate Dehydrogenase
  • LDHA protein, human
  • Ascorbic Acid
  • Epinephrine