Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer
Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer
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DOI：
10.1007/s10549-009-0621-9
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发表时间：
2010-08-01
影响因子：
3.8
通讯作者：
Reedijk, Michael
中科院分区：
文献类型：
--
作者：
Cohen, Brenda;Shimizu, Mamiko;Reedijk, Michael
Notch配体JAG 1与乳腺癌复发相关。在此，我们报告了一种基因组学方法来阐明促进乳腺癌生长的JAG 1下游机制。在对46个乳腺癌细胞系的调查中，我们发现三阴性（TN;基底和间充质ER-、PR-和Her 2-阴性）细胞系表达的JAG 1水平显著高于HER 2（+）或管腔（ER+）Her 2（-）细胞系。与所测试的管腔细胞系（T47 D和MCF 7）相反，TN乳腺癌细胞系（HCC 1143和MDA MB 231）显示出高水平的JAG 1表达和生长抑制，RNA干扰诱导的JAG 1下调。我们使用微阵列分析转染JAG 1 siRNA的TN肿瘤细胞来鉴定JAG 1调节的基因（P千分之一货币符号0.005;倍数变化千分之一日元1.5）。在鉴定的JAG 1调节基因中，发现细胞周期蛋白D1是NOTCH 1和NOTCH 3的直接靶点。我们发现，JAG 1下调减少了Notch与细胞周期蛋白D1启动子的直接结合，减少了细胞周期蛋白D1的表达，并通过细胞周期蛋白D1依赖的G1/S检查点抑制细胞周期进程。此外，我们表明，细胞周期蛋白D1和JAG 1的表达相关的TN乳腺癌表达数据集。这些数据表明，JAG 1促进细胞周期蛋白D1介导的TN乳腺癌增殖的模型。
The Notch ligand, JAG1 is associated with breast cancer recurrence. Herein, we report on a genomics approach to elucidate mechanisms downstream of JAG1 that promote breast cancer growth. In a survey of 46 breast cancer cell lines, we found that triple negative (TN; basal and mesenchymal ER-, PR-, and Her2-negative) lines express JAG1 at significantly higher levels than do HER2(+) or luminal (ER+) Her2(-) cell lines. In contrast to the luminal lines tested (T47D and MCF7), TN breast cancer cell lines (HCC1143 and MDA MB231) display high-level JAG1 expression and growth inhibition with RNA interference-induced JAG1 down-regulation. We used microarray profiling of TN tumor cells transfected with JAG1 siRNA to identify JAG1-regulated genes (P a parts per thousand currency sign 0.005; fold change a parts per thousand yen1.5). Among JAG1-regulated genes identified, cyclin D1 was found to be a direct target of NOTCH1 and NOTCH3. We show that JAG1 down-regulation reduces direct binding of Notch to the cyclin D1 promoter, reduced cyclin D1 expression and inhibition of cell cycle progression through the cyclin D1-dependant G1/S checkpoint. Furthermore, we show that cyclin D1 and JAG1 expression correlate in TN breast cancer expression datasets. These data suggest a model whereby JAG1 promotes cyclin D1-mediated proliferation of TN breast cancers.