Interferon-beta represses cancer stem cell properties in triple-negative breast cancer

Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-12, Vol.114 (52), p.13792-13797
Main Authors: Doherty, Mary R., Cheon, HyeonJoo, Junk, Damian J., Vinayak, Shaveta, Varadan, Vinay, Telli, Melinda L., Ford, James M., Stark, George R., Jackson, Mark W.
Format: Article
Language:English
Subjects:
Biological Sciences
Breast cancer
Cancer
Cell Line, Tumor
Chemotherapy
Deoxyribonucleic acid
DNA
DNA damage
Drug resistance
Epithelial cells
Epithelial-Mesenchymal Transition - drug effects
Epithelium
Female
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Genetic transformation
Humans
Immune response
Immune system
Interferon
Interferon-beta - pharmacology
Leukocyte migration
Lymphocytes
Mammary gland
Mesenchyme
Morphology
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Properties (attributes)
Proteins
Signaling
Stem cells
Surface markers
Transcription
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - metabolism
Triple Negative Breast Neoplasms - pathology
Tumor-infiltrating lymphocytes
Tumors
Vimentin
β-Interferon
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Summary:Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non–CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-β reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1713728114