C/EBPδ: friend or foe? a novel role for C/EBPδ in metastasis.

Hypoxia contributes to major aspects of cancer biology such as angiogenesis, glucose/energy metabolism, invasion and metastasis. The activation of hypoxiainducible factor 1a (HIF-1a) is a key step that promotes the transcriptional activation of target genes fundamental for these processes. In this issue of EMBO Journal, Balamurugan et al provide new insights on how hypoxia control integrates with inflammation and metastasis by describing an exciting role for the transcription factor C/EBPd in the amplification of HIF-1a signalling. The authors show that C/EBPd promotes the transcriptional repression of the tumour suppressor F-box and WD repeatdomain containing 7 protein (FBXW7), which in turn leads to mTOR protein stabilization and increased HIF-1a levels. Although C/EBPd can act as a tumour suppressor gene at early stages of cancer development, it appears to have a positive role in progression and metastasis, thus adding to the ranks of genes that exert opposing effects at early and late stages of tumorigenesis. An increasing body of evidence suggests that C/EBPd functions as a tumour suppressor (Pawar et al, 2010; Wang et al, 2010). In this issue of EMBO Journal, Balamurugan et al provide in vivo evidence that germline deletion of this gene promotes increased tumour number in transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Surprisingly, the authors report that though an increased number of primary tumours was observed in C/EBPd-null mice, a paradoxical two-fold reduction in the incidence of metastasis was seen in the same animals. After some careful detective work, Balamurugan et al came to the conclusion that the mechanism involves an intricate interplay between C/EBPd and HIF-1a. First, a link between hypoxia and C/EBPd was established by the discovery of high immunoreactivity against C/EBPd specifically in hypoxic areas of mammary tumours. Using isolated mammary tumour cells, the authors then showed that, while in WT cells HIF-1a is strongly induced under hypoxic culture conditions, cells derived from C/EBPd-null tumours fail to show such induction. Fast growing tumours outpace the ability of vasculature to deliver enough oxygen and nutrients. HIF-1a activation is critical for adaptation of cells to hypoxic stress, in part, by promoting transcriptional changes leading to anaerobic metabolism (Semenza, 2010). C/EBPd-null tumour cells fail to implement this adaptation as shown by decreased viability, glucose uptake and lactate production when subjected to hypoxia. These results seem to confirm a fundamental role of C/EBPd in the establishment of a successful adjustment to low oxygen levels. The serine-threonine protein kinase mTOR serves as a central regulator of cell metabolism, growth, proliferation and survival (Laplante and Sabatini, 2009). Oncogenic activation of this pathway by loss of function of several tumour suppressors (LKB1, PML, PTEN, TSC1/TSC2) or