title: The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer.
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.
authors.affiliation: Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mendoza-Villanueva
authors.affiliation: Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Balamurugan
authors.affiliation: Cancer Research UK, Cambridge Institute, Department of Oncology, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
authors.forename: H R
authors.initials: HR
authors.lastname: Ali
authors.affiliation: Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: S-R
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sharan
authors.affiliation: CCR Collaborative Bioinformatics Resource, Advanced Biomedical Computing Center, Leidos Biomed, Frederick National Laboratory, Frederick, MD, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Johnson
authors.affiliation: CCR Collaborative Bioinformatics Resource, Advanced Biomedical Computing Center, Leidos Biomed, Frederick National Laboratory, Frederick, MD, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Merchant
authors.affiliation: Cancer Research UK, Cambridge Institute, Department of Oncology, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
authors.forename: C
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Breakthrough Breast Cancer Unit, Institute of Cancer Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
authors.forename: G
authors.initials: G
authors.lastname: Landberg
authors.affiliation: Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sterneck
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D004848:Epithelium / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D011379:Prognosis; D055550:Protein Stability; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D051743:CCAAT-Enhancer-Binding Protein-delta; D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D000071250:Snail Family Transcription Factors; D044767:Ubiquitin-Protein Ligases; C513273:FBXW7 protein, human; C000604408:SNAI2 protein, human