Please use this identifier to cite or link to this item: https://doi.org/10.1038/onc.2011.417
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dc.titleNon-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop
dc.contributor.authorStiehl, D.P.
dc.contributor.authorBordoli, M.R.
dc.contributor.authorAbreu-Rodríguez, I.
dc.contributor.authorWollenick, K.
dc.contributor.authorSchraml, P.
dc.contributor.authorGradin, K.
dc.contributor.authorPoellinger, L.
dc.contributor.authorKristiansen, G.
dc.contributor.authorWenger, R.H.
dc.date.accessioned2014-12-12T07:12:27Z
dc.date.available2014-12-12T07:12:27Z
dc.date.issued2012-05-03
dc.identifier.citationStiehl, D.P., Bordoli, M.R., Abreu-Rodríguez, I., Wollenick, K., Schraml, P., Gradin, K., Poellinger, L., Kristiansen, G., Wenger, R.H. (2012-05-03). Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop. Oncogene 31 (18) : 2283-2297. ScholarBank@NUS Repository. https://doi.org/10.1038/onc.2011.417
dc.identifier.issn09509232
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/115203
dc.description.abstractTumor 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-2α. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF-2α-dependent and their promoters were particularly responsive to HIF-2α. The endogenous AREG promoter recruited HIF-2α in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2α-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-2α-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-2α-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-2α/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2α balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy. © 2012 Macmillan Publishers Limited All rights reserved.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1038/onc.2011.417
dc.sourceScopus
dc.subjectEGF signaling
dc.subjectgrowth factors
dc.subjectHIF target genes
dc.subjecthypoxic expression profiles
dc.subjectluminal breast cancer
dc.typeArticle
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.description.doi10.1038/onc.2011.417
dc.description.sourcetitleOncogene
dc.description.volume31
dc.description.issue18
dc.description.page2283-2297
dc.description.codenONCNE
dc.identifier.isiut000303610800004
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