Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer

Cell Metab. 2021 Mar 2;33(3):499-512.e6. doi: 10.1016/j.cmet.2021.01.018. Epub 2021 Feb 16.


Obesity is a major risk factor for adverse outcomes in breast cancer; however, the underlying molecular mechanisms have not been elucidated. To investigate the role of crosstalk between mammary adipocytes and neoplastic cells in the tumor microenvironment (TME), we performed transcriptomic analysis of cancer cells and adjacent adipose tissue in a murine model of obesity-accelerated breast cancer and identified glycine amidinotransferase (Gatm) in adipocytes and Acsbg1 in cancer cells as required for obesity-driven tumor progression. Gatm is the rate-limiting enzyme in creatine biosynthesis, and deletion in adipocytes attenuated obesity-driven tumor growth. Similarly, genetic inhibition of creatine import into cancer cells reduced tumor growth in obesity. In parallel, breast cancer cells in obese animals upregulated the fatty acyl-CoA synthetase Acsbg1 to promote creatine-dependent tumor progression. These findings reveal key nodes in the crosstalk between adipocytes and cancer cells in the TME necessary for obesity-driven breast cancer progression.

Keywords: Acsbg1; Gatm; breast cancer; creatine; hypoxia; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipose Tissue / cytology
  • Adipose Tissue / metabolism
  • Amidinotransferases / deficiency
  • Amidinotransferases / genetics
  • Amidinotransferases / metabolism
  • Animals
  • Breast Neoplasms / pathology*
  • Cell Communication / physiology*
  • Cell Line, Tumor
  • Coenzyme A Ligases / genetics
  • Coenzyme A Ligases / metabolism
  • Creatine / metabolism*
  • Diet, High-Fat
  • Female
  • Humans
  • Membrane Transport Proteins / chemistry
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / pathology*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Tumor Microenvironment


  • Membrane Transport Proteins
  • RNA, Small Interfering
  • creatine transporter
  • Amidinotransferases
  • glycine amidinotransferase
  • Coenzyme A Ligases
  • Creatine