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

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

doi:10.18632/oncotarget.8866

Jerry H Fuady, Roland H Wenger + Show 4 more

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https://doi.org/10.18632/oncotarget.8866

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Abstract

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.

Highlights

The ability of cancer cells to adapt to microenvironmental tissue hypoxia is mainly mediated by hypoxia-inducible factors (HIFs), which affect every aspect of cancer progression, comprising metabolism, proliferation, inflammation, angiogenesis, metastasis and therapy resistance [1,2,3,4]
Neither HIF1α mRNA (Figure 1B) nor hypoxically stabilized HIF-1α protein levels (Figure 1C) were significantly affected by 24 hours E2 treatment. These data suggest that HIF-2α is downregulated by E2-ERα signaling on the mRNA level, which resulted in corresponding changes on the protein levels
Hypoxia represents another major factor in breast cancer progression, and the interaction between these two signaling pathways is of major clinical importance [4]

Summary

Introduction

The ability of cancer cells to adapt to microenvironmental tissue hypoxia is mainly mediated by hypoxia-inducible factors (HIFs), which affect every aspect of cancer progression, comprising metabolism, proliferation, inflammation, angiogenesis, metastasis and therapy resistance [1,2,3,4]. We and others found different kinetics of hypoxic HIF-1α and HIF-2α protein induction and target gene expression [10, 11], further suggesting non-overlapping roles for these two related transcription factors. Estrogens are steroid hormones and represent the primary female sex hormones, regulating diverse physiological processes in reproductive, mammary, cardiovascular, osseous, hepatic, and neuronal tissues [12,13,14,15,16]. Ligand binding leads to the dissociation of heat shock proteins from the ER, which is followed by receptor dimerization and nuclear translocation. The activated dimer complex binds to estrogen response elements (EREs) located within the regulatory regions of target genes [18]

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