Vascular endothelial growth factor is a target gene for estrogen receptor and contributes to breast cancer progression
Vascular endothelial growth factor is a target gene for estrogen receptor and contributes to breast cancer progression
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DOI：
10.1007/978-0-387-69080-3_42
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发表时间：
2008-01-01
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影响因子：
--
通讯作者：
Corpet, Armelle
中科院分区：
文献类型：
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作者：
Applanat, Martine Perrot;Buteau-Lozano, Helene;Corpet, Armelle
肿瘤生长需要血管系统的发育和重塑，涉及各种生长因子和内皮受体之间的旁分泌信号传导。血管内皮生长因子（VEGF）是发育、生理和病理性新生血管形成的关键调节因子，尤其参与肿瘤生长。最近的研究表明，17 β-雌二醇（E2）通过转录激活调节乳腺癌细胞中VEGF的表达。我们研究了E-2诱导VEGF表达和VEGF控制乳腺癌血管生成的分子机制。在使用VEGF启动子-荧光素酶构建体的瞬时转染试验中，E-2增加了MCF-7细胞和与雌激素受体（ER α或ER β）共转染的MDA-MB-231中的VEGF转录活性。当用纯抗雌激素ICI 182，780或激动剂/拮抗剂他莫昔芬处理MCF-7细胞时，阳性作用被消除。我们进一步鉴定了VEGF启动子中的不完全雌激素反应元件（ERE 1520），其在使用MCF-7或MDA-MB-231核提取物的凝胶位移测定中与ER α或ERP蛋白形成复合物; ERE序列在我们的实验条件下参与VEGF的转录调节。这些结果表明，在乳腺癌（BC）细胞中，VEGF是ER α或ERP的靶基因。为了确定VEGF在人乳腺癌进展中的作用，我们产生了稳定的过表达VEGF 165的人乳腺癌细胞（MCF-7）（V165克隆）。将细胞或对照载体克隆皮下植入无胸腺小鼠中。我们的体内研究结果表明，VEGF的过度表达显着降低肿瘤摄取和增加肿瘤生长和血管生成的小鼠模型的BC。
Tumor growth requires the development and remodeling of the vascular system, involving paracrine signaling between various growth factors and endothelial receptors. Vascular endothelial growth factor (VEGF) is a key regulator of developmental, physiological and pathological neovascularization, especially involved in tumor growth. Recent studies indicate that 17 beta-estradiol (E2) modulates VEGF expression in breast cancer cells through transcriptional activation. We have investigated both the molecular mechanisms of E-2-induction of VEGF expression and of VEGF control of breast cancer angiogenesis. In transient transfection assays using the VEGF promoter-luciferase construct, E-2 increased VEGF transcriptional activity in MCF-7 cells and in MDA-MB-231 cotransfected with estrogen receptor (ER alpha or ER beta). The positive effect was abolished when MCF-7 cells were treated with the pure antiestrogen ICI 182,780 or the agonist/antagonist tamoxifen. We further identified an imperfect estrogen responsive element (ERE1520) in the VEGF promoter, which formed a complex with ER alpha or ERP proteins in gel shift assay using MCF-7 or MDA-MB-231 nuclear extracts; the ERE sequence is involved in the transcriptional regulation of VEGF in our experimental conditions. These results demonstrate that in breast cancer (BC) cells VEGF is a target gene for ERa or ERP. To determine the role of VEGF in the progression of human breast carcinoma, we generated stable human breast carcinoma cells (MCF-7) overexpressing VEGF165 (V 165 clones). Cells or control vector clones were implanted subcutaneously in athymic mice. Our in vivo findings show that overexpression of VEGF significantly decreased tumor uptake and increased tumor growth and angiogenesis in a murine model of BC.