Non-canonical HIF-2α function drives autonomous breast cancer cell growth via an AREG-EGFR/ErbB4 autocrine loop

Oncogene. 2012 May 3;31(18):2283-97. doi: 10.1038/onc.2011.417. Epub 2011 Sep 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphiregulin
  • Autocrine Communication
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / physiopathology
  • Breast Neoplasms / therapy
  • CCN Intercellular Signaling Proteins / metabolism*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease-Free Survival
  • EGF Family of Proteins
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / metabolism*
  • Female
  • Glycoproteins / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Receptor, ErbB-4
  • Repressor Proteins / metabolism*
  • Signal Transduction


  • AREG protein, human
  • Amphiregulin
  • Basic Helix-Loop-Helix Transcription Factors
  • CCN Intercellular Signaling Proteins
  • CCN5 protein, human
  • EGF Family of Proteins
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Repressor Proteins
  • endothelial PAS domain-containing protein 1
  • Epidermal Growth Factor
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-4