Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism
Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism
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DOI：
10.1677/joe-07-0198
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发表时间：
2008-02-01
影响因子：
4
通讯作者：
Perrot-Applanat, Martine
中科院分区：
文献类型：
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作者：
Buteau-Lozano, Helene;Velasco, Guillaume;Perrot-Applanat, Martine
环境化学物质可能通过扰乱内分泌功能而影响人体健康。它们在乳腺和乳腺肿瘤中的可能作用尚不清楚。既往研究表明，血管内皮生长因子（VEGF）是雌激素调控基因，是血管生成和肿瘤进展的关键因子。我们分析了在几种乳腺癌细胞中，MELN（源自MCF-7）和MELP（源自MDA-MB-231）是否受不同异种雌激素的调控，并稳定表达雌激素受体α (ER α)；这些细胞系稳定地表达雌激素反应因子（-珠蛋白）荧光素酶。染料木黄酮、双酚A （BPA）、4-（叔辛基）酚（OP）、狄氏剂和几种邻苯二甲酸酯，包括邻苯二甲酸苄丁酯（BBP）和邻苯二甲酸二乙基-2-己基酯（DEHP），首次被证明具有雌激素性。这些化合物诱导MELN和MCF-7细胞中VEGF分泌呈剂量依赖性增加；在1 ~ 10 μ M的非细胞毒浓度下观察到最大效果，并被抗雌激素ICI 182 780抑制。在ER α阴性的MDA-MB-231细胞中未观察到VEGF升高。大多数物质增加MELN细胞中VEGF转录水平。相比之下，γ -六氯环己烷、vinclozolin和邻苯二甲酸酯（邻苯二甲酸单正丁酯、邻苯二甲酸二异壬酯和邻苯二甲酸二异癸酯）在这些细胞系中对VEGF分泌和雌激素荧光素酶诱导均无效。特异性激酶抑制剂PD98059、SB203580或LY294002抑制异种雌激素诱导的VEGF反应，提示MEK、p38激酶和磷脂酰肌醇-3激酶途径的激活。我们的体外实验结果首次表明染料木素和异种雌激素（高浓度双酚a、011、狄氏剂、BBP和DEHP）通过er依赖机制上调MELN细胞中VEGF的表达。由于VEGF在体内增加毛细血管通透性和乳腺肿瘤血管生成，因此讨论了这些发现的生理学相关性。
Environmental chemicals may affect human health by disrupting endocrine function. Their possible role in the mammary gland and breast tumors is still unknown. Previous studies have demonstrated that vascular endothelial growth factor (VEGF), a key factor in angiogenesis and tumor progression, is an estrogen-regulated gene. We analyzed whether VEGF expression is regulated by different xenoestrogens in several breast cancer cells, MELN (derived from MCF-7) and MELP (derived from MDA-MB-231) and stably expressing estrogen receptor alpha (ER alpha); these cell lines stably express estrogen response element (beta-globin)luciferase. Genistein, bisphenol A (BPA), 4-(tert-octyl)phenol (OP), dieldrin, and several phthalates, including benzyl butyl phthalate (BBP) and di-ethyl-2-hexyle phthalate (DEHP), were first shown to be estrogenic. These compounds induced a dose-dependent increase of VEGF secretion in MELN and MCF-7 cells; maximal effect was observed at 1-10 mu M non-cytotoxic concentrations and was inhibited by the antiestrogen ICI 182 780. VEGF increase was not observed in ER alpha-negative MDA-MB-231 cells. Most substances increased VEGF transcript levels in MELN cells. In contrast, gamma-hexachlorocyclohexane, vinclozolin, and the phthalates (mono-n-butyl ester phthalic acid, di-isononyle phthalate, and di-isodecyle phthalate) were ineffective on both VEGF secretion and estrogenic luciferase induction in these cell lines. Specific kinase inhibitors PD98059, SB203580, or LY294002 suppressed the xenoestrogen-induced VEGF response, suggesting activation of MEK, p38 kinase, and phosphatidylinositol-3-kinase pathways. Our in vitro results show for the first time that genistein and xenoestrogens (BPA, 011, dieldrin, BBP, and DEHP at high concentrations) up-regulate VEGF expression in MELN cells by an ER-dependent mechanism. Since VEGF increases capillary permeability and breast tumor angiogenesis in vivo, the physiological relevance of these findings is discussed.