Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Canada.
Breast Cancer Res Treat. 2010 Aug;123(1):113-24. doi: 10.1007/s10549-009-0621-9. Epub 2009 Nov 14.
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 <or= 0.005; fold change >or=1.5). 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.
Notch 配体 JAG1 与乳腺癌复发有关。在此，我们报告了一种基因组学方法，以阐明 JAG1 下游促进乳腺癌生长的机制。在对 46 种乳腺癌细胞系的调查中，我们发现三阴性（TN；基底和间质 ER-、PR-和 Her2-阴性）细胞系表达 JAG1 的水平明显高于 HER2(+)或腔（ER(+)) Her2(-)细胞系。与测试的腔系（T47D 和 MCF7）不同，TN 乳腺癌细胞系（HCC1143 和 MDA MB231）显示高水平的 JAG1 表达和生长抑制，用 RNA 干扰诱导 JAG1 下调。我们使用 JAG1 siRNA 转染的 TN 肿瘤细胞的微阵列分析来鉴定 JAG1 调节的基因（P <or= 0.005；倍数变化 >or=1.5）。在鉴定的 JAG1 调节基因中，细胞周期蛋白 D1 被发现是 NOTCH1 和 NOTCH3 的直接靶标。我们表明，JAG1 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 依赖性 G1/S 检查点抑制细胞周期进程。此外，我们表明在 TN 乳腺癌表达数据集中，cyclin D1 和 JAG1 的表达相关。这些数据表明，JAG1 促进了 TN 乳腺癌中 cyclin D1 介导的增殖。
