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Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

Oncogene volume 30, pages 548–560 (2011)Cite this article

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Abstract

Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxia-inducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-α protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF-2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer.

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Acknowledgements

We thank P Spielmann for excellent technical assistance, K Wollenick, TF Lüscher, PJ Ratcliffe (University of Oxford, Oxford, UK), SB Lee (National Institutes of Health, Bethesda, MD, USA), DA Chan (University of California, San Francisco, CA, USA) for gifts of antibodies, cells and plasmids and D Neri (Institute of Pharmaceutical Sciences, ETH Zürich, Switzerland) for helpful discussions. This work was supported by the Swiss National Science Foundation and Krebsliga des Kantons Zürich (GC).

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Authors and Affiliations

  1. Institute of Physiology and Zürich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland

    M R Bordoli, D P Stiehl, L Borsig, R H Wenger & G Camenisch

  2. Department of Pathology, University Hospital Zürich, Zürich, Switzerland

    G Kristiansen, S Hausladen & P Schraml

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  1. M R Bordoli
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  2. D P Stiehl
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Correspondence to R H Wenger.

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Bordoli, M., Stiehl, D., Borsig, L. et al. Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis. Oncogene 30, 548–560 (2011). https://doi.org/10.1038/onc.2010.433

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