GATA3 protein as a MUC1 transcriptional regulator in breast cancer cells.
GATA3 protein as a MUC1 transcriptional regulator in breast cancer cells.
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DOI：
10.1186/bcr1617
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Aldaz CM
中科院分区：
文献类型：
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作者：
Abba MC;Nunez MI;Colussi AG;Croce MV;Segal-Eiras A;Aldaz CM
最近的研究表明，GATA结合蛋白（加塔）家族成员（GATA 4和GATA 5）可能在胃肠道上皮粘蛋白基因（MUC 2、MUC 3和MUC 4）的转录上调中起关键作用。锌指GATA 3转录因子参与乳腺上皮细胞的生长调控和分化。在SAGE（基因表达系列分析）研究中，我们观察到乳腺癌中GATA 3和MUC 1 mRNA表达之间存在有趣的显著相关性。因此，我们设计了本研究，以阐明是否MUC 1的表达是由GATA 3在乳腺癌细胞中的调节。MUC 1基因的启动子序列分析鉴定了5'侧翼区的6个加塔顺式共有元件（GATA 1、GATA 3和4个GATA样序列）。染色质免疫沉淀和电泳迁移率变动分析，以研究存在的功能GATA 3结合位点。GATA 3和MUC 1表达用GATA 3敲低测定法在体外分析。此外，GATA 3和MUC 1基因的表达通过实时RT-PCR和免疫组化乳腺癌特异性组织芯片进行了分析。我们证实了在MCF 7细胞系中MUC 1启动子区存在功能性GATA 3结合位点。我们确定GATA 3敲低试验导致MCF 7和T47 D细胞中MUC 1蛋白表达减少。此外，我们检测到在正常乳腺上皮和乳腺癌中GATA 3和MUC 1基因在mRNA和蛋白水平上的表达具有统计学显著相关性（p = 0.01）。GATA 3表达也与乳腺癌中雌激素受体和孕激素受体状态（p = 0.0001）和肿瘤分级（p = 0.004）高度相关。我们的研究提供的证据表明，GATA 3可能是一个介导的转录上调MUC 1表达在一些乳腺癌。
Recent studies have demonstrated that members of the GATA-binding protein (GATA) family (GATA4 and GATA5) might have pivotal roles in the transcriptional upregulation of mucin genes (MUC2, MUC3 and MUC4) in gastrointestinal epithelium. The zinc-finger GATA3 transcription factor has been reported to be involved in the growth control and differentiation of breast epithelial cells. In SAGE (serial analysis of gene expression) studies we observed an intriguing significant correlation between GATA3 and MUC1 mRNA expression in breast carcinomas. We therefore designed the present study to elucidate whether MUC1 expression is regulated by GATA3 in breast cancer cells. Promoter sequence analysis of the MUC1 gene identified six GATA cis consensus elements in the 5' flanking region (GATA1, GATA3 and four GATA-like sequences). Chromatin immunoprecipitation and electrophoretic mobility-shift assays were employed to study the presence of a functional GATA3-binding site. GATA3 and MUC1 expression was analyzed in vitro with a GATA3 knockdown assay. Furthermore, expression of GATA3 and MUC1 genes was analyzed by real-time RT-PCR and immunohistochemistry on breast cancer-specific tissue microarrays. We confirmed the presence of a functional GATA3-binding site on the MUC1 promoter region in the MCF7 cell line. We determined that GATA3 knockdown assays led to a decrease in MUC1 protein expression in MCF7 and T47D cells. In addition, we detected a statistically significant correlation in expression between GATA3 and MUC1 genes at the mRNA and protein levels both in normal breast epithelium and in breast carcinomas (p = 0.01). GATA3 expression was also highly associated with estrogen receptor and progesterone receptor status (p = 0.0001) and tumor grade (p = 0.004) in breast carcinomas. Our study provides evidence indicating that GATA3 is probably a mediator for the transcriptional upregulation of MUC1 expression in some breast cancers.