Ras/ets-2 Pathway in Breast Cancer Progression

大量证据表明，ras信号通路在人类乳腺癌的多阶段进展中发挥作用，尽管这些通路的激活机制通常不包括激活ras基因的突变。我们已经确定Ets-2是ras途径的核靶点，可以持续激活基因表达，最近的研究表明Ets-2也可以通过信号依赖的方式抑制基因表达。基因靶标包括EGF配体家族的成员，如 HB-EGF，以及一组胞外蛋白，包括尿激酶型纤溶酶原激活剂、基质分解素1/MMP3、MMP9和基质金属蛋白酶-MT1。这些靶基因的一致性表明，ras/ETS-2通路可能在肿瘤细胞发生的上皮-间充质转化过程中被激活，并与更具转移性的表型相一致。然而，在肿瘤进展过程中，这些靶基因也在肿瘤微环境中的其他类型的细胞中表达，特别是在巨噬细胞和间质成纤维细胞中。这导致了ras/ETS-2通路可能在肿瘤微环境中的几种细胞类型中被激活，并可能在肿瘤进展的不同阶段发挥不同的作用。我们建议使用条件性基因敲除方法去除乳腺肿瘤微环境中巨噬细胞和间质成纤维细胞中的ETS-2。我们还建议建立原位小鼠模型，使我们能够研究ETS-2间质成纤维细胞在肿瘤转移中的作用。结合本计划项目资助的其他两个项目，我们还将研究RAS/ETS-2、PTEN和RB/E2F途径之间的相互作用。这些实验将使我们更好地理解ras/ETS-2通路在乳腺肿瘤进展过程中以时间和空间特异性模式协调基因表达的作用。

A substantial body of evidence indicates that ras signaling pathways play a role in multi-stage progression of human breast cancer, even though the mechanisms of activation of these pathways does not usually include activating mutations in the ras genes. We have identified ets-2 as a nuclear target of ras pathways that can persistently activate gene expression, and more recently have demonstrated that ets-2 can also repress gene expression in a signaling-dependent fashion. Gene targets include members of the EGF ligand family, such as HB-EGF, as well as a group of extracellular proteases including urokinase plasminogen activator, stromelysin 1/MMP3, MMP9 and MMP-MT1. The identity of these target genes suggests that the ras/ets-2 pathway may be activated during the epithelial-mesenchymal transition that occurs in the tumor cell and coincides with a more metastatic phenotype. However, these target genes are also expressed in other types of cells in the tumor microenvironment during tumor progression, particularly in macrophages and stromal fibroblasts. This leads to the proposition that the ras/ets-2 pathway may be activated in several cell types in the tumor microenvironment and may play distinct roles in different stages of tumor progression. We propose to use conditional gene knockout approaches to remove ets-2 in macrophages and stromal fibroblasts in the mammary tumor microenvironment. We also propose to develop orthotopic mouse models that will allow us to study the role of ets-2 stromal fibroblasts during tumor metastasis. In combination with the other two Projects in this Program Project Grant, we will also study interactions between the ras/ets-2, Pten and Rb/E2F pathways. These experiments will give us a better understanding of the role of the ras/ets-2 pathway in coordinating expression of genes in a temporal and spatial specific pattern during mammary tumor progression.