Role of c-Myb during Prolactin-Induced Signal Transducer and Activator of Transcription 5a Signaling in Breast Cancer Cells
Role of c-Myb during Prolactin-Induced Signal Transducer and Activator of Transcription 5a Signaling in Breast Cancer Cells
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DOI：
10.1210/en.2008-1079
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发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Clevenger, Charles V.
中科院分区：
文献类型：
--
作者：
Fang, Feng;Rycyzyn, Michael A.;Clevenger, Charles V.
催乳素（PRL）参与乳腺癌的发病机制，部分通过催乳素受体（PRLr）相关Janus激酶2（Jak 2）/信号转导和转录激活因子5（Stat 5）信号传导复合物介导其功能。为了阐明Stat 5a在乳腺癌中的调控机制，采用转录因子-转录因子（TF-TF）阵列分析来鉴定相关的转录调控因子。这些分析揭示了PRL诱导的Stat 5a与转录因子和原癌基因c-Myb的关联。使用来自T47 D和MCF 7乳腺癌细胞的裂解物的炎性共免疫沉淀研究揭示了这些转录因子之间的PRL诱导的关联。c-Myb的异位表达增强了PRL诱导的复合和合成Stat 5a应答荧光素酶报告基因的表达。染色质免疫沉淀分析还揭示了PRL诱导的c-Myb和内源性Stat 5a反应性CISH启动子之间的关联，这与CISH基因产物在RNA和蛋白质水平上的表达增强有关。小干扰RNA介导的c-Myb敲低损害了PRL诱导的5个Stat 5应答基因的mRNA表达。不能激活c-Myb应答报告基因表达的c-Myb DNA结合缺陷突变体保持了增强Stat 5a应答报告基因的能力。在细胞水平上，c-Myb的异位表达导致T47 D增殖的增加。总之，这些结果表明，c-Myb增强Stat 5a驱动的基因表达，可能作为Stat 5a共激活剂，在人类乳腺癌。（内分泌学150：1597-1606，2009）
Implicated in the pathogenesis of breast cancer, prolactin (PRL) mediates its function in part through the prolactin receptor (PRLr)-associated Janus kinase 2 (Jak2)/signal transducer and activator of transcription 5 (Stat5) signaling complex. To delineate the mechanisms of Stat5a regulation in breast cancer, transcription factor-transcription factor (TF-TF) array analysis was employed to identify associated transcriptional regulators. These analyses revealed a PRL-inducible association of Stat5a with the transcription factor and protooncogene c-Myb. Confirmatory co-immunoprecipitation studies using lysates from both T47D and MCF7 breast cancer cells revealed a PRL-inducible association between these transcription factors. Ectopic expression of c-Myb enhanced the PRL-induced expression from both composite and synthetic Stat5a-responsive luciferase reporters. Chromatin immunoprecipitation assays also revealed a PRL-inducible association between c-Myb and endogenous Stat5a-responsive CISH promoter, which was associated with an enhanced expression of CISH gene product at the RNA and protein levels. Small interfering RNA-mediated c-Myb knockdown impaired the PRL-induced mRNA expression of five Stat5-responsive genes. DNA binding-defective mutants of c-Myb, incapable of activating expression from a c-Myb-responsive reporter, maintained their ability to enhance a Stat5a-responsive reporter. At a cellular level, ectopic expression of c-Myb resulted in an increase in T47D proliferation. Taken together, these results indicate that c-Myb potentiates Stat5a-driven gene expression, possibly functioning as a Stat5a coactivator, in human breast cancer. (Endocrinology 150: 1597-1606, 2009)