Tumor hypoxia is one hallmark of solid tumors. Thus, tumor growth is highly affected by the transcription factor hypoxia-inducible factor (HIF) and the HIF-dependent hypoxia-inducible gene expression. The stability of the HIFa subunit is regulated by oxygen-dependent hydroxylation, which is facilitated by three prolyl-hydroxylase domain (PHD) enzymes. In our work we have shown, that PHD2 significantly affects the response of tumor cells towards chemotherapy as well as tumor cell migration. Regarding tumor growth, however, we observed a bimodal effect of PHD2 by performing xenograft experiments. Whereas knock down of PHD2 supports tumor growth of the non-invasive MCF-7 breast carcinoma cells, PHD2 knock down significantly impairs tumor growth of the invasive MDA-MB 231 cells. Using a non-biased RNA screen we found SPP-1 to be significantly down regulated in the MDA-MB 231 PHD2 knock down cells compared to the wild type cells, while its expression remained unchanged in the MCF-7 knock down cells. These data point to a cell line specific influence of PHD2 on tumor growth and cell adhesion. Additional molecular studies revealed a connection between PHD2 and TGF-b1, which in turn is involved in regulating the SPP-1 expression. This might in part explain the observed down regulation of the SPP-1 expression in the MDA-MB 231 PHD2 knock down cells.