| Literature DB >> 32284542 |
Sushil Kumar1, Ratnesh Kumar Srivastava1, Snahlata Singh1, Ajeya Nandi1, Gatha Thacker1, Hemma Murali1, Sabrina Kim1, Mary Baldeon1, John Tobias2, Mario Andres Blanco1, Rizwan Saffie2, M Raza Zaidi3, Satrajit Sinha4, Luca Busino2, Serge Y Fuchs1, Rumela Chakrabarti5.
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.Entities:
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Year: 2020 PMID： 32284542 PMCID： PMC8237104 DOI： 10.1038/s41556-020-0495-y
Source DB: PubMed Journal: Nat Cell Biol ISSN： 1465-7392 Impact factor: 28.824