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The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer
Hypoxia and inflammatory cytokines like interleukin-6 (IL6) are strongly linked to cancer progression, and signal in part through the transcription factor Ccaat/enhancer binding protein δ (C/EBPδ, CEBPD), which has been shown to promote mesenchymal features and malignant progression of glioblastoma....
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112156/ https://www.ncbi.nlm.nih.gov/pubmed/27181204 http://dx.doi.org/10.1038/onc.2016.156 |
Sumario: | Hypoxia and inflammatory cytokines like interleukin-6 (IL6) are strongly linked to cancer progression, and signal in part through the transcription factor Ccaat/enhancer binding protein δ (C/EBPδ, CEBPD), which has been shown to promote mesenchymal features and malignant progression of glioblastoma. Here we report a different role for C/EBPδ in breast cancer. We found that the C/EBPδ protein is expressed in normal breast epithelial cells and in low-grade cancers. C/EBPδ protein (but not mRNA) expression correlates with estrogen receptor (ER+) and progesterone receptor (PGR) expression and longer progression-free survival of breast cancer patients. Specifically in ER+ breast cancers, CEBPD–but not the related CEBPB–mRNA in combination with IL6 correlated with lower risk of progression. Functional studies in cell lines showed that ERα promotes C/EBPδ expression at the level of protein stability by inhibition of the FBXW7 pathway. Furthermore, we found that C/EBPδ attenuates cell growth, motility and invasiveness by inhibiting expression of the SNAI2 (Slug) transcriptional repressor, which leads to expression of the cyclin dependent kinase inhibitor CDKN1A (p21(CIP1/WAF1)). These findings identify a molecular mechanism by which ERα signaling reduces the aggressiveness of cancer cells, and demonstrate that C/EBPδ can have different functions in different types of cancer. Furthermore, our results support a potentially beneficial role for the IL-6 pathway specifically in ER+ breast cancer and call for further evaluation of the role of intra-tumoral IL-6 expression and of which cancers might benefit from current attempts to target the IL-6 pathway as a therapeutic strategy. |
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