Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling

Nat Cell Biol. 2020 May;22(5):591-602. doi: 10.1038/s41556-020-0495-y. Epub 2020 Apr 13.

Abstract

Triple-negative breast cancer (TNBC) is characterized by a high degree of immune infiltrate in the tumour microenvironment, which may influence the fate of TNBC cells. We reveal that loss of the tumour suppressive transcription factor Elf5 in TNBC cells activates intrinsic interferon-γ (IFN-γ) signalling, promoting tumour progression and metastasis. Mechanistically, we find that loss of the Elf5-regulated ubiquitin ligase FBXW7 ensures stabilization of its putative protein substrate IFN-γ receptor 1 (IFNGR1) at the protein level in TNBC. Elf5low tumours show enhanced IFN-γ signalling accompanied by an increase of immunosuppressive neutrophils within the tumour microenvironment and increased programmed death ligand 1 expression. Inactivation of either programmed death ligand 1 or IFNGR1 elicited a robust anti-tumour and/or anti-metastatic effect. A positive correlation between ELF5 and FBXW7 expression and a negative correlation between ELF5, FBXW7 and IFNGR1 expression in the tumours of patients with TNBC strongly suggest that this signalling axis could be exploited for patient stratification and immunotherapeutic treatment strategies for Elf5low patients with TNBC.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / physiology*
  • DNA-Binding Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7 / metabolism*
  • Female
  • HEK293 Cells
  • Humans
  • Interferon-gamma / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Metastasis / pathology*
  • Receptors, Interferon / metabolism*
  • Signal Transduction / physiology
  • Transcription Factors / metabolism*
  • Triple Negative Breast Neoplasms / metabolism*
  • Tumor Microenvironment / physiology

Substances

  • DNA-Binding Proteins
  • ELF5 protein, human
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Receptors, Interferon
  • Transcription Factors
  • interferon gamma receptor
  • Interferon-gamma