Positive Feedback Activation of Estrogen Receptors by the CXCL12-CXCR4 Pathway
Positive Feedback Activation of Estrogen Receptors by the CXCL12-CXCR4 Pathway
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DOI：
10.1158/0008-5472.can-08-4924
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Tremblay, Andre
中科院分区：
文献类型：
--
作者：
Sauve, Karine;Lepage, Julie;Tremblay, Andre
通过雌激素受体ER α和ER β诱导雌激素调节的基因转录在乳腺癌的发展和生长中起重要作用。趋化因子受体CXCR 4及其配体CXCL 12/基质细胞衍生因子I（SDF-1）的高表达也与侵袭性乳腺肿瘤表型相关。在这里，我们描述了在人乳腺癌细胞中CXCR 4/SDF-1信号通路和ER转录能力之间的正调控环。用SDF-1处理乳腺癌MCF-7细胞增加了ER转录活性和ER靶基因的表达，包括SDF-1本身。这些作用被阻断的抗雌激素ICI-182780和CXCR 4沉默，相反，雌激素诱导的基因表达和MCF-7细胞的生长受损的CXCR 4抑制。ER α和EP β在CXCR 4存在的情况下被SDF-1激活，并通过组成型活性CXCR 4的过表达激活，表明CXCR 4向两种受体发出信号。特别是，ER β能够翻译SDF-1对其自身表达的影响，以及在他莫昔芬存在下增强含有基因细胞周期蛋白D1和c-Myc的激活蛋白I（AP-1）。这与雌激素反应性和AP-1元件的反应性启动子的ER β占用增加相关。Ser-87是ER β中一个保守的丝裂原活化蛋白激酶位点，SDF-1高度磷酸化，揭示了AF-1结构域在响应CXCR 4活化中的重要作用。这些结果确定了CXCR 4/SDF-1和ER α/ER β信号通路之间的一个完整的自分泌回路，该回路决定了ER依赖性基因的表达和乳腺癌细胞的生长。[Cancer Res 2009;69（14）：5793-800]
Induction of estrogen-regulated gene transcription by estrogen receptors ER alpha and ER beta plays an important role in breast cancer development and growth. High expression of the chemokine receptor CXCR4 and its ligand CXCL12/stromal cell-derived factor I (SDF-1) has also been correlated with aggressive breast tumor phenotypes. Here, we describe a positive regulatory loop between the CXCR4/SDF-1 signaling pathway and ER transcriptional competence in human breast cancer cells. Treatment of breast carcinoma MCF-7 cells with SDF-1 increased ER transcriptional activity and expression of ER target genes, including SDF-1 itself. These effects were blocked by the antiestrogen ICI-182780 and by CXCR4 silencing and, conversely, estrogen-induced gene expression and growth of MCF-7 cells were impaired on CXCR4 inhibition. Both ER alpha and EP beta were activated by SDF-1 in the presence of CXCR4 and by overexpression of a constitutively active CXCR4, indicating that CXCR4 signals to both receptors. In particular, ER beta was able to translate the effects of SDF-1 on its own expression, as well as enhance activator protein I (AP-1) containing genes cyclin D1 and c-Myc in the presence of tamoxifen. This correlated with an increased ER beta occupancy of responsive promoters at both estrogen-responsive and AP-1 elements. Ser-87, a conserved mitogen-activated protein kinase site in ER beta, was highly phosphorylated by SDF-1, revealing an essential role of the AF-1 domain in response to CXCR4 activation. These results identify a complete autocrine loop between the CXCR4/SDF-1 and ER alpha/ER beta signaling pathways that dictates ER-dependent gene expression and growth of breast cancer cells. [Cancer Res 2009;69(14):5793-800]