title: The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis.
abstract: Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer-binding protein-δ (C/EBPδ, CEBPD) is an inflammatory response gene and candidate tumour suppressor, but its physiological role in tumourigenesis in vivo is unknown. Here, we demonstrate a tumour suppressor function of C/EBPδ using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBPδ is necessary for efficient tumour metastasis. We show that C/EBPδ is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBPδ-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBPδ supports CXCR4 expression. On the other hand, C/EBPδ directly inhibits expression of the tumour suppressor F-box and WD repeat-domain containing 7 gene (FBXW7, FBW7, AGO, Cdc4), encoding an F-box protein that promotes degradation of the mammalian target of rapamycin (mTOR). Consequently, C/EBPδ enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1α (HIF-1α), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia.
authors.affiliation: Laboratory of Cell and Developmental Signalling, CCR, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Kuppusamy
authors.initials: K
authors.lastname: Balamurugan
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Hsin-Hwa
authors.initials: HH
authors.lastname: Tsai
authors.forename: Shikha
authors.initials: S
authors.lastname: Sharan
authors.forename: Miriam
authors.initials: M
authors.lastname: Anver
authors.forename: Robert
authors.initials: R
authors.lastname: Leighty
authors.forename: Esta
authors.initials: E
authors.lastname: Sterneck
mesh_terms: D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D044783:F-Box Proteins / Q000096:biosynthesis*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation; D006019:Glycolysis; D000860:Hypoxia; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000503:physiopathology / Q000556:secondary*; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000503:physiopathology; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; D051743:CCAAT-Enhancer-Binding Protein-delta; D044767:Ubiquitin-Protein Ligases