Liver-Type Glutaminase GLS2 Is a Druggable Metabolic Node in Luminal-Subtype Breast Cancer

Cell Rep. 2019 Oct 1;29(1):76-88.e7. doi: 10.1016/j.celrep.2019.08.076.

Abstract

Efforts to target glutamine metabolism for cancer therapy have focused on the glutaminase isozyme GLS. The importance of the other isozyme, GLS2, in cancer has remained unclear, and it has been described as a tumor suppressor in some contexts. Here, we report that GLS2 is upregulated and essential in luminal-subtype breast tumors, which account for >70% of breast cancer incidence. We show that GLS2 expression is elevated by GATA3 in luminal-subtype cells but suppressed by promoter methylation in basal-subtype cells. Although luminal breast cancers resist GLS-selective inhibitors, we find that they can be targeted with a dual-GLS/GLS2 inhibitor. These results establish a critical role for GLS2 in mammary tumorigenesis and advance our understanding of how to target glutamine metabolism in cancer.

Keywords: 968; BPTES; CB-839; GLS; breast cancer; glutaminase; glutamine metabolism GLS2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Cell Line
  • Cell Line, Tumor
  • DNA Methylation / genetics
  • Female
  • GATA3 Transcription Factor / metabolism
  • Genes, Tumor Suppressor / physiology
  • Glutaminase / metabolism*
  • Glutamine / metabolism
  • HEK293 Cells
  • Humans
  • Liver / metabolism*
  • MCF-7 Cells
  • Mice
  • Promoter Regions, Genetic / genetics

Substances

  • GATA3 Transcription Factor
  • Glutamine
  • GLS2 protein, human
  • Glutaminase