PMID- 21927022
OWN - NLM
STAT- MEDLINE
DCOM- 20121101
LR  - 20190816
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 31
IP  - 18
DP  - 2012 May 3
TI  - Non-canonical HIF-2alpha function drives autonomous breast cancer cell growth via an 
      AREG-EGFR/ErbB4 autocrine loop.
PG  - 2283-97
LID - 10.1038/onc.2011.417 [doi]
AB  - Tumor progression is intrinsically tied to the clonal selection of tumor cells 
      with acquired phenotypes allowing to cope with a hostile microenvironment. 
      Hypoxia-inducible factors (HIFs) master the transcriptional response to local 
      tissue hypoxia, a hallmark of solid tumors. Here, we report significantly longer 
      patient survival in breast cancer with high levels of HIF-2alpha. Amphiregulin (AREG) 
      and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly 
      HIF-2alpha-dependent and their promoters were particularly responsive to HIF-2alpha. The 
      endogenous AREG promoter recruited HIF-2alpha in the absence of a classical HIF-DNA 
      interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG 
      expression in HIF-2alpha-depleted cells was accompanied by reduced activation of 
      epidermal growth factor (EGF) receptor family members. Apparently opposing 
      results from patient and in vitro data point to an HIF-2alpha-dependent 
      auto-stimulatory tumor phenotype that, while promoting EGF signaling in cellular 
      models, increased the survival of diagnosed and treated human patients. Our 
      findings suggest a model where HIF-2alpha-mediated autocrine growth signaling in 
      breast cancer sustains a state of cellular self-sufficiency, thereby masking 
      unfavorable microenvironmental growth conditions, limiting adverse selection and 
      improving therapy efficacy. Importantly, HIF-2alpha/AREG/WISP2-expressing tumors were 
      associated with luminal tumor differentiation, indicative of a better response to 
      classical treatments. Shifting the HIF-1/2alpha balance toward an HIF-2-dominated 
      phenotype could thus offer a novel approach in breast cancer therapy.
FAU - Stiehl, D P
AU  - Stiehl DP
AD  - Institute of Physiology and Zurich Center for Human Physiology (ZIHP), University 
      of Zurich, Zurich, Switzerland. daniel.stiehl@uzh.ch
FAU - Bordoli, M R
AU  - Bordoli MR
FAU - Abreu-Rodriguez, I
AU  - Abreu-Rodriguez I
FAU - Wollenick, K
AU  - Wollenick K
FAU - Schraml, P
AU  - Schraml P
FAU - Gradin, K
AU  - Gradin K
FAU - Poellinger, L
AU  - Poellinger L
FAU - Kristiansen, G
AU  - Kristiansen G
FAU - Wenger, R H
AU  - Wenger RH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110919
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (CCN Intercellular Signaling Proteins)
RN  - 0 (CCN5 protein, human)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Repressor Proteins)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ERBB4 protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, ErbB-4)
SB  - IM
MH  - Amphiregulin
MH  - Autocrine Communication
MH  - Basic Helix-Loop-Helix Transcription Factors/*metabolism
MH  - Breast Neoplasms/*metabolism/pathology/physiopathology/therapy
MH  - CCN Intercellular Signaling Proteins/*metabolism
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Disease-Free Survival
MH  - EGF Family of Proteins
MH  - Epidermal Growth Factor/metabolism
MH  - ErbB Receptors/*metabolism
MH  - Female
MH  - Glycoproteins/*metabolism
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/*metabolism
MH  - Receptor, ErbB-4
MH  - Repressor Proteins/*metabolism
MH  - Signal Transduction
EDAT- 2011/09/20 06:00
MHDA- 2012/11/02 06:00
CRDT- 2011/09/20 06:00
PHST- 2011/09/20 06:00 [entrez]
PHST- 2011/09/20 06:00 [pubmed]
PHST- 2012/11/02 06:00 [medline]
AID - onc2011417 [pii]
AID - 10.1038/onc.2011.417 [doi]
PST - ppublish
SO  - Oncogene. 2012 May 3;31(18):2283-97. doi: 10.1038/onc.2011.417. Epub 2011 Sep 19.