title: Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop.
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.
authors.affiliation: Institute of Physiology and Zürich Center for Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland. daniel.stiehl@uzh.ch
authors.forename: D P
authors.initials: DP
authors.lastname: Stiehl
authors.forename: M R
authors.initials: MR
authors.lastname: Bordoli
authors.forename: I
authors.initials: I
authors.lastname: Abreu-Rodríguez
authors.forename: K
authors.initials: K
authors.lastname: Wollenick
authors.forename: P
authors.initials: P
authors.lastname: Schraml
authors.forename: K
authors.initials: K
authors.lastname: Gradin
authors.forename: L
authors.initials: L
authors.lastname: Poellinger
authors.forename: G
authors.initials: G
authors.lastname: Kristiansen
authors.forename: R H
authors.initials: RH
authors.lastname: Wenger
mesh_terms: D066258:Amphiregulin; D019898:Autocrine Communication; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D055511:CCN Intercellular Signaling Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018572:Disease-Free Survival; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D066247:Receptor, ErbB-4; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D066258:Amphiregulin; D051792:Basic Helix-Loop-Helix Proteins; D055511:CCN Intercellular Signaling Proteins; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D066247:Receptor, ErbB-4; D012097:Repressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C587848:AREG protein, human; C413323:CCN5 protein, human; C587689:ERBB4 protein, human