Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer

• Published in: Oncotarget Vol. 8; no. 6; pp. 9885 - 9898
• Main Authors: Kozlova, Nina, Wottawa, Marieke, Katschinski, Dörthe Magdalena, Kristiansen, Glen, Kietzmann, Thomas
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 07.02.2017
• Subjects: Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Epidermal Growth Factor - pharmacology; ErbB Receptors - agonists; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases - genetics; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Phosphorylation; Protein Binding; Protein Stability; Proteolysis; Research Paper; RNA Interference; Signal Transduction - drug effects; Time Factors; Transfection; Tumor Hypoxia; Tumor Microenvironment; breast cancer; PHD2; EGFR; EGFR-signaling; hypoxia signaling
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.14241

Clinical studies in breast cancer suggest important associations between intratumoral hypoxia, the upregulation of epidermal growth factor receptor (EGFR or HER1), hypoxia-inducible factor 1α (HIF-1α), and reduced patient survival. However, direct molecular links between EGFR and the hypoxia signaling system are not yet established. Since the oxygen sensor hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is considered to be the main HIF-1α regulator, we hypothesized that PHD2 and EGFR may be interconnected at the molecular level. By analyzing samples from 313 breast cancer patients, we found that EGFR is a first clinicopathological parameter positively correlating with PHD2. Mechanistically, we identified PHD2 as a direct binding partner of EGFR and show that PHD2 regulates EGFR stability as well as its subsequent signaling in breast carcinoma cells. Overall, we introduce for the first time the direct crosstalk between the oxygen sensor PHD2 and EGFR-mediated tumorigenesis in breast cancer.