Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748193/ https://www.ncbi.nlm.nih.gov/pubmed/29229854 http://dx.doi.org/10.1073/pnas.1713728114 |
_version_ | 1783289372215345152 |
---|---|
author | Doherty, Mary R. Cheon, HyeonJoo Junk, Damian J. Vinayak, Shaveta Varadan, Vinay Telli, Melinda L. Ford, James M. Stark, George R. Jackson, Mark W. |
author_facet | Doherty, Mary R. Cheon, HyeonJoo Junk, Damian J. Vinayak, Shaveta Varadan, Vinay Telli, Melinda L. Ford, James M. Stark, George R. Jackson, Mark W. |
author_sort | Doherty, Mary R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5748193 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-57481932018-01-09 Interferon-beta represses cancer stem cell properties in triple-negative breast cancer Doherty, Mary R. Cheon, HyeonJoo Junk, Damian J. Vinayak, Shaveta Varadan, Vinay Telli, Melinda L. Ford, James M. Stark, George R. Jackson, Mark W. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2017-12-26 2017-12-11 /pmc/articles/PMC5748193/ /pubmed/29229854 http://dx.doi.org/10.1073/pnas.1713728114 Text en Copyright © 2017 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Doherty, Mary R. Cheon, HyeonJoo Junk, Damian J. Vinayak, Shaveta Varadan, Vinay Telli, Melinda L. Ford, James M. Stark, George R. Jackson, Mark W. Interferon-beta represses cancer stem cell properties in triple-negative breast cancer |
title | Interferon-beta represses cancer stem cell properties in triple-negative breast cancer |
title_full | Interferon-beta represses cancer stem cell properties in triple-negative breast cancer |
title_fullStr | Interferon-beta represses cancer stem cell properties in triple-negative breast cancer |
title_full_unstemmed | Interferon-beta represses cancer stem cell properties in triple-negative breast cancer |
title_short | Interferon-beta represses cancer stem cell properties in triple-negative breast cancer |
title_sort | interferon-beta represses cancer stem cell properties in triple-negative breast cancer |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748193/ https://www.ncbi.nlm.nih.gov/pubmed/29229854 http://dx.doi.org/10.1073/pnas.1713728114 |
work_keys_str_mv | AT dohertymaryr interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT cheonhyeonjoo interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT junkdamianj interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT vinayakshaveta interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT varadanvinay interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT tellimelindal interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT fordjamesm interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT starkgeorger interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer AT jacksonmarkw interferonbetarepressescancerstemcellpropertiesintriplenegativebreastcancer |