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

Abstract

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.

• Authors: Mary R Doherty, HyeonJoo Cheon, Damian J Junk, Shaveta Vinayak, Vinay Varadan, Melinda L Telli, James M Ford, George R Stark, Mark W Jackson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 52 Pg. 13792-13797 (12 26 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 29229854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 the Author(s). Published by PNAS.

Chemical References

• Neoplasm Proteins
• Interferon-beta

Topics

• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interferon-beta (pharmacology)
• Neoplasm Proteins (biosynthesis, genetics)
• Neoplastic Stem Cells (metabolism, pathology)
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)