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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

Oncogene volume 35, pages 6166–6176 (2016)Cite this article

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Abstract

Hypoxia and inflammatory cytokines like interleukin-6 (IL-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 (p21CIP1/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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Acknowledgements

We are thankful to the Laboratory Animal Sciences Program (Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research) for excellent support, especially Donna Butcher and Glenn Summers for superb services, and Bao Tran and Jyoti Shetty (Leidos Biomedical Research, Inc.) for mRNA-Seq data. We also thank Elise Nilsson for excellent technical assistance. We thank student interns Katherine L Zhou and Yasmin Y Lachir for their valuable contributions, Linda Miller for preparation of plasmids, and Allen Kane and Joseph Meyer (Leidos Biomedical Research, Inc.) for preparing the figures for publication. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute and in part with Federal Funds from the Frederick National Laboratory (NIH) under contract no. HHSN261200800001E. DM-V was supported in part by a scholarship from the National Council on Science and Technology (CONACYT), Mexico. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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Author notes

  1. S-R Kim

    Present address: 5Current address: Division of Biotechnology Review and Research IV, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.,

  2. G Landberg

    Present address: 6Current address: Department of Pathology, Sahlgrenska Cancer Center, Gothenburg University, Medicinaregatan 1F, Gothenburg 405 30, Sweden.,

Authors and Affiliations

  1. Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    D Mendoza-Villanueva, K Balamurugan, S-R Kim, S Sharan & E Sterneck

  2. Department of Oncology, Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK

    H R Ali & C Caldas

  3. CCR Collaborative Bioinformatics Resource, Advanced Biomedical Computing Center, Leidos Biomed, Frederick National Laboratory, Frederick, MD, USA

    R C Johnson & A S Merchant

  4. Breakthrough Breast Cancer Unit, Institute of Cancer Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    G Landberg

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Mendoza-Villanueva, D., Balamurugan, K., Ali, H. et al. The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer. Oncogene 35, 6166–6176 (2016). https://doi.org/10.1038/onc.2016.156

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