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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-49926

Stiehl, D P; Bordoli, M R; Abreu-Rodríguez, I; Wollenick, K; Schraml, P; Gradin, K; Poellinger, L; Kristiansen, G; Wenger, R H (2012). Non-canonical HIF-2alpha function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop. Oncogene, 31(18):2283-2297.

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Tumor progression is intrinsically tied to the clonal
selection of tumor cells with acquired phenotypes allowing
to cope with a hostile microenvironment. Hypoxiainducible
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-2a.
Amphiregulin (AREG) and WNT1-inducible signaling
pathway protein-2 (WISP2) expression was strongly HIF-
2a-dependent and their promoters were particularly
responsive to HIF-2a. The endogenous AREG promoter
recruited HIF-2a in the absence of a classical HIF–DNA
interaction motif, revealing a novel mechanism of gene
regulation. Loss of AREG expression in HIF-2a-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-2a-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-
2a-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-2a/AREG/WISP2-expressing
tumors were associated with luminal tumor differentiation,
indicative of a better response to classical treatments.
Shifting the HIF-1/2a balance toward an HIF-2-
dominated phenotype could thus offer a novel approach in
breast cancer therapy.


16 citations in Web of Science®
18 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Deposited On:18 Oct 2011 11:01
Last Modified:06 Dec 2013 13:46
Publisher:Nature Publishing Group
Funders:Swiss National Science Foundation, Swedish Cancer Society and European Union, Metoxia, COST Action TD0901 HypoxiaNet
Publisher DOI:10.1038/onc.2011.417
PubMed ID:21927022

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