Ras/ets-2 Pathway in Breast Cancer Progression

大量证据表明，ras信号通路在人乳腺癌的多阶段进展中发挥作用，即使这些通路的激活机制通常不包括ras基因的激活突变。我们已经确定ets-2作为ras通路的核靶点，可以持续激活基因表达，最近又证明ets-2也可以以信号依赖的方式抑制基因表达。基因靶点包括EGF配体家族的成员，如 如HB-EGF，以及一组细胞外蛋白酶，包括尿激酶纤溶酶原激活物、基质溶解素1/MMP 3、MMP 9和MMP-MT 1。这些靶基因的身份表明，ras/ets-2途径可能被激活的上皮间质转化过程中发生在肿瘤细胞和符合更多的转移表型。然而，这些靶基因也在肿瘤进展期间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基质成纤维细胞中。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，并且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的方法，以消除ets-2的巨噬细胞和基质成纤维细胞在乳腺肿瘤微环境。我们还建议开发原位小鼠模型，这将使我们能够研究ets-2基质成纤维细胞在肿瘤转移过程中的作用。结合其他两个项目，我们还将研究ras/ets-2，Pten和Rb/E2 F通路之间的相互作用。这些实验将使我们更好地了解ras/ets-2通路在乳腺肿瘤进展过程中协调基因表达的时空特异性模式。

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.