Estrogen-dependent downregulation of hypoxia-inducible factor (HIF)-2α in invasive breast cancer cells.
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.
Institute of Physiology and Zurich Centre for Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Jerry H
JH
Fuady
Institute of Physiology and Zurich Centre for Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Katrin
K
Gutsche
Institute of Physiology and Zurich Centre for Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Sara
S
Santambrogio
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
Zsuzsanna
Z
Varga
Institute of Physiology, University of Duisburg-Essen, Essen, Germany.
David
D
Hoogewijs
Institute of Physiology and Zurich Centre for Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Roland H
RH
Wenger
D000107:Acetylation; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D046888:Tissue Array Analysis; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000099162:Endothelial PAS Domain-Containing Protein 1; C506487:ESR1 protein, human; C497442:HIF1A protein, human; C508053:ERBB2 protein, human
ERα; HER2; histone deacetylation; hormone therapy; tumor oxygenation