Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor-Regulated Angiogenesis in Triple-Negative Breast Cancer
Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor-Regulated Angiogenesis in Triple-Negative Breast Cancer
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DOI：
10.1158/1541-7786.mcr-12-0428
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发表时间：
2013-05-01
影响因子：
5.2
通讯作者：
Miyamoto, Shingo
中科院分区：
文献类型：
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作者：
Yotsumoto, Fusanori;Tokunaga, Eriko;Miyamoto, Shingo
肝素结合egf样生长因子（HB-EGF）是几种促血管生成因子之一，代表了三阴性乳腺癌（TNBC）患者可能的治疗靶点。然而，HB-EGF在TNBC中促进肿瘤侵袭性的作用尚不清楚。为了研究参与TNBC肿瘤发生的特定基因和途径，我们分析了两种TNBC细胞系在二维培养（2DC）和三维培养（3DC）以及肿瘤异种移植模型中的基因表达变化。我们发现，与2DC相比，3DC和肿瘤异种移植物中HB-EGF、VEGFA和血管生成素样4 （ANGPTL4）同时上调。我们发现HB-EGF通过缺氧诱导因子-1 α和NF-kappa b的转录调节VEGFA或ANGPTL4的表达。此外，抑制VEGFA或ANGPTL4的表达会增强HB-EGF的表达，强调了这种血管生成网络背后独特的调节回路。与单独敲除VEGFA或ANGPTL4相比，靶向敲除HB-EGF通过降低VEGFA和ANGPTL4的表达，显著抑制TNBC异种移植模型中的肿瘤形成。在TNBC患者中，VEGFA或ANGPTL4表达也与HB-EGF表达显著相关。低浓度外源性添加HB-EGF强烈激活内皮细胞的增殖、血管管的形成和血管的通透性，与高剂量的VEGFA和ANGPTL4类似。综上所述，这些结果表明HB-EGF通过协调调节肿瘤血管生成的分子层次，在TNBC中肿瘤侵袭性的获得中起着关键作用。AACR (C) 2013人。
Heparin-binding EGF-like growth factor (HB-EGF) is one of several proangiogenic factors and represents a possible therapeutic target for patients with triple-negative breast cancer (TNBC). However, the role of HB-EGF in promoting tumor aggressiveness in TNBC remains unclear. To investigate specific genes and pathways involved in TNBC tumorigenesis, we profiled gene expression changes in two TNBC cell lines under two-dimensional culture (2DC) and three-dimensional culture (3DC) and in a tumor xenograft model. We identified simultaneous upregulation of HB-EGF, VEGFA, and angiopoietin-like 4 (ANGPTL4) in 3DC and tumor xenografts, compared with 2DC. We show that HB-EGF regulates the expression of VEGFA or ANGPTL4 via transcriptional regulation of hypoxia-inducible factor-1 alpha and NF-kappa B. Furthermore, suppression of VEGFA or ANGPTL4 expression enhanced HB-EGF expression, highlighting a unique regulatory loop underlying this angiogenesis network. Targeted knockdown of HB-EGF significantly suppressed tumor formation in a TNBC xenograft model, compared with individual knockdown of either VEGFA or ANGPTL4, by reducing the expression of both VEGFA and ANGPTL4. In patients with TNBC, VEGFA or ANGPTL4 expression was also significantly correlated with HB-EGF expression. Low concentrations of exogenously added HB-EGF strongly activated the proliferation of endothelial cells, tube formation, and vascular permeability in blood vessels, in a similar fashion to high doses of VEGFA and ANGPTL4. Taken together, these results suggest that HB-EGF plays a pivotal role in the acquisition of tumor aggressiveness in TNBC by orchestrating a molecular hierarchy regulating tumor angiogenesis. (C)2013 AACR.