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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