期刊
ONCOGENE
卷 31, 期 18, 页码 2283-2297出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.417
关键词
hypoxic expression profiles; luminal breast cancer; growth factors; HIF target genes; EGF signaling
资金
- Swiss National Science Foundation [31003A_129962/1]
- Swedish Cancer Society
- European Union, Metoxia
- COST Action [TD0901 HypoxiaNet]
- Swiss National Science Foundation (SNF) [31003A_129962] Funding Source: Swiss National Science Foundation (SNF)
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-2 alpha. Amphiregulin (AREG) and WNT1-inducible signaling pathway protein-2 (WISP2) expression was strongly HIF-2 alpha-dependent and their promoters were particularly responsive to HIF-2 alpha. The endogenous AREG promoter recruited HIF-2 alpha in the absence of a classical HIF-DNA interaction motif, revealing a novel mechanism of gene regulation. Loss of AREG expression in HIF-2 alpha-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-2 alpha-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-2 alpha-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-2 alpha/AREG/WISP2-expressing tumors were associated with luminal tumor differentiation, indicative of a better response to classical treatments. Shifting the HIF-1/2 alpha balance toward an HIF-2-dominated phenotype could thus offer a novel approach in breast cancer therapy. Oncogene (2012) 31, 2283-2297; doi:10.1038/onc.2011.417; published online 19 September 2011
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