Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Rm 170 E&R Building, 401 Haddon Avenue, Camden, NJ 01806, USA.
Breast Cancer Res Treat. 2010 Jul;122(1):55-63. doi: 10.1007/s10549-009-0517-8. Epub 2009 Sep 2.
Meta-analyses of microarray data indicate that GATA3 is co-expressed with estrogen receptor alpha (ER) in breast cancer cells. While the significance of this remains unclear, it is thought that GATA3 may serve as a prognostic indicator in breast tumors and may play a role in ER signaling. Recently, reciprocal regulation of GATA3 and ER transcription was demonstrated, suggesting that control of their expression is intertwined. We sought to determine whether GATA3 and ER expression was also coordinately regulated at other levels. Unlike ER, GATA3 was not under epigenetic control and was not re-expressed in the presence of DNMT or HDAC inhibitors in ER/GATA3-negative cells. However, like ER, these inhibitors decreased GATA3 expression in ER/GATA3-positive cell lines. We have previously reported that ER mRNA stability is increased through binding of the RNA-binding protein HuR/ELAV1 to the 3'untranslated region (UTR) and that DNMT and HDAC inhibitors reduce ER expression by altering this interaction. Biotin pull-down assays using a biotinylated GATA3 RNA probe confirmed that HuR also binds to the GATA3 3'UTR. Inhibition of HuR using siRNA probes decreased GATA3 mRNA, mRNA stability and protein expression, indicating that HuR plays a role in regulating GATA3 expression. Inhibition of either HuR or GATA3 reduced cell growth of MCF7 cells. Based on our findings, it is clear that coordinate regulation of ER and GATA3 occurs, however differences do exist. These findings may aid in identification of new targets that control cell growth of breast cancer cells.
基于微阵列数据的荟萃分析表明，GATA3 与乳腺癌细胞中的雌激素受体 alpha（ER）共同表达。虽然其意义尚不清楚，但人们认为 GATA3 可能作为乳腺癌肿瘤的预后指标，并可能在 ER 信号转导中发挥作用。最近，证明了 GATA3 和 ER 转录的相互调控，表明它们的表达控制是交织在一起的。我们试图确定 GATA3 和 ER 表达是否在其他水平上也协调调节。与 ER 不同，GATA3 不受表观遗传控制，并且在 ER/GATA3-阴性细胞中不存在 DNMT 或 HDAC 抑制剂时不会重新表达。然而，与 ER 一样，这些抑制剂降低了 ER/GATA3-阳性细胞系中的 GATA3 表达。我们之前报道过，通过 RNA 结合蛋白 HuR/ELAV1 与 3'非翻译区（UTR）的结合，增加了 ER mRNA 的稳定性，并且 DNMT 和 HDAC 抑制剂通过改变这种相互作用降低了 ER 的表达。使用生物素化 GATA3 RNA 探针的生物素下拉测定证实 HuR 也与 GATA3 3'UTR 结合。使用 siRNA 探针抑制 HuR 降低了 GATA3 mRNA、mRNA 稳定性和蛋白质表达，表明 HuR 在调节 GATA3 表达中发挥作用。抑制 HuR 或 GATA3 均可降低 MCF7 细胞的细胞生长。根据我们的发现，很明显 ER 和 GATA3 的协调调节发生了，但是存在差异。这些发现可能有助于确定控制乳腺癌细胞生长的新靶标。
