Interferon-beta represses cancer stem cell properties in triple-negative breast cancer.
Proc Natl Acad Sci U S A
; 114(52): 13792-13797, 2017 12 26.
Article
en En
| MEDLINE
| ID: mdl-29229854
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-ß) 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-ß, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-ß 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-ß reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Madre Neoplásicas
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Regulación Neoplásica de la Expresión Génica
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Interferón beta
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Transición Epitelial-Mesenquimal
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Neoplasias de la Mama Triple Negativas
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Proteínas de Neoplasias
Límite:
Female
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Humans
Idioma:
En
Año:
2017
Tipo del documento:
Article