Research Papers:

This article has been corrected. Correction in: Oncotarget. 2017; 8(12):20516.

Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells

Jerry H. Fuady, Katrin Gutsche, Sara Santambrogio, Zsuzsanna Varga, David Hoogewijs and Roland H. Wenger _

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Oncotarget. 2016; 7:31153-31165. https://doi.org/10.18632/oncotarget.8866

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Jerry H. Fuady1, Katrin Gutsche1, Sara Santambrogio1, Zsuzsanna Varga2, David Hoogewijs3, Roland H. Wenger1

1Institute of Physiology and Zurich Centre for Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

2Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland

3Institute of Physiology, University of Duisburg-Essen, Essen, Germany

Correspondence to:

Roland H. Wenger, e-mail: [email protected]

Keywords: ERα, HER2, histone deacetylation, hormone therapy, tumor oxygenation

Received: December 13, 2015     Accepted: March 31, 2016     Published: April 20, 2016


The involvement of estrogen (E2) and hypoxia in tumor progression is well established. Hypoxia has been reported to activate and degrade estrogen receptor alpha (ERα) in breast cancer cells. Furthermore, E2 has been shown to regulate hypoxia-inducible factor (HIF)-1α protein, but its role in HIF-2α regulation remains largely unexplored. In this study, we found that both HIF-2α mRNA and protein were down-regulated in ER positive but not ER negative breast cancer cells upon treatment with E2. The analysis of 690 samples derived from 608 mixed and 82 triple-negative breast cancer patients revealed that high nuclear HIF-2α tumor levels are associated with a worse prognosis specifically in human epidermal growth factor receptor 2 (HER2) and hormone receptor positive patients. Consistently, ERα/HER2 positive breast cancer cells displayed less pronounced downregulation of HIF-2α by E2. Experiments using a histone deacetylase inhibitor indicate that the E2 mediated decrease in HIF-2α mRNA is due to transcriptional repression. A functional estrogen response element (ERE) was identified in the first intron of the gene encoding HIF-2α (EPAS1), suggesting transcriptional co-repressor recruitment by ERα. Our results demonstrate a novel modulation of HIF-2α in breast cancer cells, explaining the opposing regulation between HIF-1α and HIF-2α in hormone-responsive breast cancer.

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