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|Title:||Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop||Authors:||Stiehl, D.P.
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|
|Appears in Collections:||Staff Publications|
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