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Please use this identifier to cite or link to this item: http://repository.iitr.ac.in/handle/123456789/20072
Title: Loss of ELF5–FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling
Authors: Singh S.
Kumar, Sushil
Srivastava R.K.
Nandi A.
Thacker G.
Murali H.
Kim S.
Baldeon M.
Tobias J.
Blanco M.A.
Saffie R.
Zaidi M.R.
Sinha S.
Busino L.
Fuchs S.Y.
Chakrabarti R.
Published in: Nature Cell Biology
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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Citation: Nature Cell Biology, 22(5): 591-602
URI: https://doi.org/10.1038/s41556-020-0495-y
http://repository.iitr.ac.in/handle/123456789/20072
Issue Date: 2020
Publisher: Nature Research
Keywords: F box/WD repeat containing protein 7
gamma interferon
gamma interferon receptor 1
programmed death 1 ligand 1
STAT3 protein
transcription factor
transcription factor Elf5
ubiquitin protein ligase
unclassified drug
DNA binding protein
ELF5 protein, human
F box/WD repeat containing protein 7
FBXW7 protein, human
gamma interferon
gamma interferon receptor
interferon receptor
transcription factor
animal cell
animal experiment
animal model
animal tissue
Article
cancer prognosis
cell loss
controlled study
distant metastasis free survival
drug efficacy
epithelium cell
female
human
immunohistochemistry
immunosuppressive treatment
lung metastasis
metastasis
metastasis potential
mouse
neutrophil
nonhuman
overall survival
phenotype
priority journal
protein expression
protein function
protein stability
RNA sequencing
signal transduction
survival rate
survival time
triple negative breast cancer
tumor growth
tumor microenvironment
tumor volume
tumor xenograft
animal
Bagg albino mouse
cell line
cell proliferation
HEK293 cell line
metabolism
metastasis
pathology
physiology
signal transduction
triple negative breast cancer
tumor cell line
Animals
Cell Line
Cell Line, Tumor
Cell Proliferation
DNA-Binding Proteins
F-Box-WD Repeat-Containing Protein 7
Female
HEK293 Cells
Humans
Interferon-gamma
Mice
Mice, Inbred BALB C
Neoplasm Metastasis
Receptors, Interferon
Signal Transduction
Transcription Factors
Triple Negative Breast Neoplasms
Tumor Microenvironment
ISSN: 14657392
Author Scopus IDs: 57189686345
57213855617
6603663872
57216244266
57021593500
57216364425
57204683725
57216372871
7202182919
56733790800
57200689664
57193396546
7403739042
6602435324
57203074493
16149432900
Author Affiliations: Singh, S., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Kumar, S., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Srivastava, R.K., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Nandi, A., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Thacker, G., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Murali, H., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Kim, S., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Baldeon, M., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Tobias, J., Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Blanco, M.A., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Saffie, R., Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Zaidi, M.R., Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
Sinha, S., Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, United States
Busino, L., Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Fuchs, S.Y., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Chakrabarti, R., Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
Funding Details: We thank L. King (University of Pennsylvania) for critical reading of the manuscript and helpful discussions. We thank A. Minn (University of Pennsylvania) for helpful discussions. We thank the Penn Vet Comparative Pathology Core for assistance with embedding, sectioning and consultation on tumour sample analysis. We thank Y. Kang (Princeton University) for the HEK293T, EpRas, 4T1, LM2 and BT549 cell lines. We thank S. Ran (Southern Illinois University) for the HCC1806 cell line. We thank the Eastern Division of the Cooperative Human Tissue Network at The University of Pennsylvania for providing human breast cancer fixed tissues from patients. We thank A. Welm (University of Utah) for the PDX tumour tissues. We thank the members of the Flow Cytometry Core at the Children’s Hospital of Philadelphia and University of Pennsylvania. We thank the Penn Vet Imaging Core for confocal microscopy. This work was supported by grants from the American Cancer Society, an NCI-K22 grant to R.C. (K22CA193661-01) and an NCI-R01 (R01 CA237243-01A1) grant to R.C. American Cancer Society, ACS: K22CA193661-01, R01 CA237243-01A1; National Cancer Institute, NCI: K22CA193661, R01CA193711
Corresponding Author: Chakrabarti, R.; Department of Biomedical Sciences, United States; email: rumela@vet.upenn.edu
Appears in Collections:Journal Publications [BT]

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