Human cancers converge at the HIF-2α oncogenic axis

Franovic, Aleksandra; Holterman, Chet E.; Payette, Josianne

doi:10.1073/pnas.0906432106

Cited by 121 publications

(98 citation statements)

References 45 publications

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“…No receptor activation was observed in serum-starved cells similarly stimulated with recombinant WISP2 (data not shown). While our work was in progress, another study reported similarly reduced EGFR phosphorylation in human glioma, lung and colon carcinoma cell lines depleted of HIF-2a, postulating a widespread mechanism of HIF-2a-mediated growth control in human cancers (Franovic et al, 2009). In line with this study, we found reduced bromodeoxyuridine incorporation in shHIF2A cells when compared with parental MCF-7 cultures under both normoxic and hypoxic conditions (Supplementary Figure S4c).…”

Section: Immunohistochemical Analyses Of Ca9 and Glut1supporting

confidence: 86%

“…Such disparate proliferation characteristics of cells cultured in vitro or grown as xenografts in vivo have been described previously for A549 lung carcinoma cells with reduced levels of HIF-2a (Franovic et al, 2009;Mazumdar et al, 2010). Cancer cells interact with the surrounding microenvironment by secretion of a variety of growth factors, partially mediated by an HIF-2a-specific transcriptional pathway.…”

Section: Discussionsupporting

confidence: 55%

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

et al. 2011

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Tumor progression is intrinsically tied to the clonal selection of tumor cells with acquired phenotypes allowing to cope with a hostile microenvironment. Hypoxiainducible 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-2a. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF2a-dependent and their promoters were particularly responsive to HIF-2a. The endogenous AREG promoter recruited HIF-2a in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2a-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-2a-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 HIF2a-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-2a/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2a balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy.

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Section: Immunohistochemical Analyses Of Ca9 and Glut1supporting

confidence: 86%

Section: Discussionsupporting

confidence: 55%

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

et al. 2011

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“…Interestingly, our results contrast directly with those from a recent report in which HIF-2α inhibition in A549 cells, as well as in HCT116 colon carcinoma and U87MG glioblastoma cells, actually reduced xenograft tumor growth (31). The nature of these disparate results is not clear, as identical shRNA sequences were used; however, our data are supported by two important controls.…”

Section: Discussioncontrasting

confidence: 57%

HIF-2α deletion promotes Kras-driven lung tumor development

Mazumdar

Hickey

Pant

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

105

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. The oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators HIF-1α and HIF-2α are overexpressed in many human NSCLCs, and constitutive HIF-2α activity can promote murine lung tumor progression, suggesting that HIF proteins may be effective NSCLC therapeutic targets. To investigate the consequences of inhibiting HIF activity in lung cancers, we deleted Hif-1α or Hif-2α in an established Kras G12D -driven murine NSCLC model. Deletion of Hif-1α had no obvious effect on tumor growth, whereas Hif-2α deletion resulted in an unexpected increase in tumor burden that correlated with reduced expression of the candidate tumor suppressor gene Scgb3a1 (HIN-1). Here, we identify Scgb3a1 as a direct HIF-2α target gene and demonstrate that HIF-2α regulates Scgb3a1 expression and tumor formation in human Kras G12D -driven NSCLC cells. AKT pathway activity, reported to be repressed by Scgb3a1, was enhanced in HIF-2α-deficient human NSCLC cells and xenografts. Finally, a direct correlation between HIF-2α and SCGB3a1 expression was observed in approximately 70% of human NSCLC samples analyzed. These data suggest that, whereas HIF-2α overexpression can contribute to NSCLC progression, therapeutic inhibition of HIF-2α below a critical threshold may paradoxically promote tumor growth by reducing expression of tumor suppressor genes, including Scgb3a1.hypoxia | inducible mouse model | non-small cell lung cancer | tumor suppressor

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“…These data suggest that normoxic, basal HIF-2 levels are sufficient for amphiregulin gene expression which is not further induced by hypoxic stabilization of HIF-2a. Supporting this hypothesis, it has been shown that HIF-2 is slightly more abundant in normoxic and mildly hypoxic cells than HIF-1 (Wiesener et al, 1998) and a recent report demonstrated that the HIF-2-specific target gene, CITED2, was maximally expressed under normoxic conditions (Franovic et al, 2009). Furthermore, it has been shown that the vascular endothelial-cadherin gene is not regulated by hypoxic conditions, but the vascular endothelial-cadherin promoter is nevertheless activated by HIF-2 together with the Ets-1 transcription factor (Le Bras et al, 2007).…”

Section: Discussionmentioning

confidence: 91%

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

et al. 2010

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Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxiainducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-a protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF-2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer.

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Human cancers converge at the HIF-2α oncogenic axis

Cited by 121 publications

References 45 publications

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

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

HIF-2α deletion promotes Kras-driven lung tumor development

Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis

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