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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....

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Autores principales: Mendoza-Villanueva, Daniel, Balamurugan, Kuppusamy, Ali, H. Raza, Kim, Su-Ryun, Sharan, Shikha, Johnson, Randall C., Merchant, Anand S., Caldas, Carlos, Landberg, Göran, Sterneck, Esta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
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
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author Mendoza-Villanueva, Daniel
Balamurugan, Kuppusamy
Ali, H. Raza
Kim, Su-Ryun
Sharan, Shikha
Johnson, Randall C.
Merchant, Anand S.
Caldas, Carlos
Landberg, Göran
Sterneck, Esta
author_facet Mendoza-Villanueva, Daniel
Balamurugan, Kuppusamy
Ali, H. Raza
Kim, Su-Ryun
Sharan, Shikha
Johnson, Randall C.
Merchant, Anand S.
Caldas, Carlos
Landberg, Göran
Sterneck, Esta
author_sort Mendoza-Villanueva, Daniel
collection PubMed
description 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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spelling pubmed-51121562016-11-17 The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer Mendoza-Villanueva, Daniel Balamurugan, Kuppusamy Ali, H. Raza Kim, Su-Ryun Sharan, Shikha Johnson, Randall C. Merchant, Anand S. Caldas, Carlos Landberg, Göran Sterneck, Esta Oncogene Article 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. 2016-05-16 2016-12-01 /pmc/articles/PMC5112156/ /pubmed/27181204 http://dx.doi.org/10.1038/onc.2016.156 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Mendoza-Villanueva, Daniel
Balamurugan, Kuppusamy
Ali, H. Raza
Kim, Su-Ryun
Sharan, Shikha
Johnson, Randall C.
Merchant, Anand S.
Caldas, Carlos
Landberg, Göran
Sterneck, Esta
The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer
title The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer
title_full The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer
title_fullStr The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer
title_full_unstemmed The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer
title_short The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression, and associates with good prognosis in breast cancer
title_sort c/ebpδ protein is stabilized by estrogen receptor α activity, inhibits snai2 expression, and associates with good prognosis in breast cancer
topic Article
url 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
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