Estrogen regulation of thrombospondin-1 in human breast cancer cells.
Estrogen regulation of thrombospondin-1 in human breast cancer cells.
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DOI：
10.1002/ijc.24373
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发表时间：
2009-09-01
影响因子：
6.4
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Hyder SM;Liang Y;Wu J
血小板反应蛋白-1 （TSP-1）是一种大的细胞外基质蛋白，其表达与血管生成和肿瘤生长的调节有关。研究人员已经描述了TSP-1的促血管生成和抗血管生成特性，但目前尚不清楚TSP-1表达在人类乳腺癌生长和进展中的作用。由于雌激素导致许多乳腺癌的进展，而雌二醇（E2）下调TSP-1受体，我们研究了TSP-1是否受雌激素调节并参与肿瘤进展。E2在体外3 ~ 6 h内诱导T47-D和MCF-7乳腺癌细胞中TSP-1的表达；这种诱导被抗雌激素的ICI 182780阻断，表明雌激素受体（ER）是这种作用所必需的。此外，E2以er - α依赖的方式引起肿瘤细胞产生TSP-1蛋白。E2介导的TSP-1 RNA诱导是剂量依赖性的，并被放线菌素D阻断，表明E2对TSP-1的反应至少部分是转录性的。用缺失的TSP-1启动子进行转染研究，在人类TSP-1启动子中发现了一个雌激素响应区域，位于转录起始位点上游-2200至-1792 bp之间。一种针对TSP-1的抗体在体内和体外均能抑制e2依赖性MCF-7细胞的增殖。一组乳腺癌细胞在低浓度的外源性TSP-1存在下增殖，而高浓度的TSP-1则抑制增殖。real-time PCR分析显示E2还以er依赖的方式诱导未成熟去卵巢小鼠正常乳腺中TSP-1 mRNA的表达。总之，我们报告了新的观察结果，即雌激素受体阳性乳腺癌细胞中TSP-1的产生直接受雌激素控制，并且释放的蛋白具有促生长调节功能。因此，我们提出TSP-1可能是早期肿瘤抗肿瘤治疗的一个治疗靶点。
Expression of thrombospondin-1 (TSP-1), a large extracellular matrix protein, has been associated with modulation of angiogenesis and tumor growth. Both pro- and anti-angiogenic properties of TSP-1 have been described, and the role of TSP-1 expression in the growth and progression of human breast cancer is not clear. Because estrogens cause progression of many breast cancers, and estradiol (E2) downregulates a TSP-1 receptor, we examined whether TSP-1 is regulated by estrogen and involved in tumor progression. E2 induced TSP-1 expression in T47-D and MCF-7 breast cancer cells in vitro within 3-6 h; the induction was blocked by the anti-estrogen ICI 182,780, indicating that estrogen receptors (ER) are necessary for this effect. Furthermore, E2 caused the production of TSP-1 protein from tumor cells in an ER-alpha–dependent manner. The E2-mediated TSP-1 RNA induction was dose-dependent and blocked by actinomycin D, indicating that the response to E2 was at least partly transcriptional. Transfection studies with deletion constructs of the TSP-1 promoter identified an estrogen-responsive region in the human TSP-1 promoter, located between -2200 and -1792 bp upstream of the transcription start site. An antibody against TSP-1 restricted the proliferation of E2-dependent MCF-7 cells in vitro and in vivo. A panel of breast cancer cells proliferated in the presence of low concentrations of exogenous TSP-1, whereas higher concentrations inhibited proliferation. A real-time PCR analysis showed that E2 also induced TSP-1 mRNA in the normal mammary glands of immature ovariectomized mice in an ER-dependent manner. In summary, we report the novel observation that TSP-1 production is directly controlled by estrogens in ER-positive breast cancer cells, and the released protein has pro-growth regulatory functions. Consequently, we propose that TSP-1 could be a therapeutic target for anti-tumor therapy in early-stage tumors.
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