The tumour suppressor C/EBPδ inhibits FBXW7 expression and promotes mammary tumour metastasis

Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer-binding protein-delta (C/EBP delta, 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/EBP delta using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBP delta is necessary for efficient tumour metastasis. We show that C/EBP delta is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBP delta-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBP delta supports CXCR4 expression. On the other hand, C/EBP delta 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/EBP delta enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1 alpha (HIF-1 alpha), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia. The EMBO Journal (2010) 29, 4106-4117. doi: 10.1038/emboj.2010.280; Published online 12 November 2010