Please use this identifier to cite or link to this item: https://doi.org/10.1038/onc.2011.417
Title: Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop
Authors: Stiehl, D.P.
Bordoli, M.R.
Abreu-Rodríguez, I.
Wollenick, K.
Schraml, P.
Gradin, K.
Poellinger, L. 
Kristiansen, G.
Wenger, R.H.
Keywords: EGF signaling
growth factors
HIF target genes
hypoxic expression profiles
luminal breast cancer
Issue Date: 3-May-2012
Citation: Stiehl, 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
Abstract: 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-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.
Source Title: Oncogene
URI: http://scholarbank.nus.edu.sg/handle/10635/115203
ISSN: 09509232
DOI: 10.1038/onc.2011.417
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