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A statistical analysis performed on 86 DCIS lesions from 9 patients confirmed a significant correlation between increased CA9 and FoxO3A staining towards the necrotic core of the tumours (Supplementary Table S7; Supplementary Figure S14). In order to test whether the inability of FoxO3A knockdown cells to successfully adapt metabolism and promote survival in hypoxia would also impact the growth of xenograft tumours in vivo, Ctrl and FoxO3A knockdown cell clones were inoculated in nude mice and tumour growth was monitored over 33 days. The growth of the HeLa xenografts was significantly impaired by the knockdown http://www.selleck.cn/products/ipi-145-ink1197.html of FoxO3A (P http://www.selleckchem.com/products/byl719.html balance in favour of glycolysis. An example of a fused PET and computer tomography (CT) image of a FoxO3A knockdown and a control tumour is depicted in Figure 8D. Immunoblots on protein extracts from the xenograft tumours confirmed the knockdown of FoxO3A and demonstrated elevated protein levels of MRPL12 as well as of cleaved caspase 3 in the knockdown tumours (Figure 8C). Consistent with this, http://www.selleckchem.com/products/SB-431542.html stainings of xenograft tumour sections for cleaved caspase 3 by immunofluorescence showed an increase in positive staining foci in the FoxO3A knockdown tumours compared with control tumours (Supplementary Figure S15A and B). Moreover, RNA extracted from the tumours confirmed significantly increased mRNA expression of the selected mitochondrial genes in both FoxO3A-KD#1 and FoxO3A-KD#2 tumours compared with their control counterparts (Figure 8E). In this study, we have shown that FoxO3A plays an important role in the transcriptional program that facilitates metabolic adaptation in hypoxia. Not only does FoxO3A contribute markedly to the upregulation of many hypoxia-induced genes but, importantly, also plays a crucial role in the hypoxic repression of a substantial number of nuclear-encoded mitochondrial genes. Previous studies have elucidated a number of different, specific mechanisms by which HIF-1 can adapt metabolism to hypoxic conditions.