Planar cell polarity pathway contribution to breast cancer metastasis

平面细胞极性(PCP)通路通过介导细胞，在胚胎发育中发挥核心作用。 适当的组织结构所需的运动事件。越来越多的证据表明，PCP途径是 被一些实体肿瘤利用来促进其侵袭和转移潜力。同样，上皮细胞- 间充质转化(EMT)是一个在发育过程中广泛参与的细胞程序，细胞在发育过程中失去 它们的上皮特征，包括尖-基极性和细胞-细胞相互作用，并获得迁移和 侵袭性属性呈现出更多的间充质干细胞性质。众所周知，实体瘤细胞 让EMT参与转移的启动。拟议的研究的目的是研究一种分子 平衡这两条发育途径之间的联系，以辨别EMT-PCP轴的程度 有助于未转化和转化的乳腺细胞的运动性和侵袭性，并有助于 揭示一种新的有助于抑制PCP途径的分子机制。我们假设 EMT诱导剂参与Vangl依赖的平面细胞极性通路，促进运动性和 未转化和转化的乳腺上皮细胞的侵袭性，并促进乳腺癌 转移。目标1将首先检查乳腺细胞中EMT诱导对以下成分的调节程度 PCP途径，然后评估PCP途径的关键组成部分是否是EMT所必需的。 诱导乳腺细胞运动和侵袭。Aim 1研究的一个子集也将尝试区分 PCP信号转导调节EMT。目标2将详细研究一种新的PCP负调控机制， Vangl相关E3泛素连接酶Nrdp1通过抑制PCP信号通路的假说 在乳腺上皮和癌细胞中介导DVL家族蛋白的K63多泛素化。目标3将 研究核心的PCP组分Vangl2是否有助于乳腺癌的转移 转基因和原位移植的小鼠基底乳腺癌模型。圆满完成 这些研究将揭示两个发育程序之间的新联系，这两个程序由 肿瘤细胞在促进恶性肿瘤中的作用，并将评估这种协同作用在促进 乳腺癌是恶性肿瘤。

The planar cell polarity (PCP) pathway plays central roles in embryonic development by mediating cellular motility events required for proper tissue structuring. Accumulating evidence suggests that the PCP pathway is exploited by some solid tumors to promote their invasiveness and metastatic potential. Likewise, the epithelial- mesenchymal transition (EMT) is a cellular program widely engaged during development whereby cells lose their epithelial character, including apico-basal polarity and cell-cell interactions, and gain migratory and invasive properties to take on a more mesenchymal stem cell nature. It is well established that solid tumor cells engage EMT in the initiation of metastasis. The purpose of the proposed studies is to examine on a molecular level the link between these two developmental pathways, to discern the degree to which an EMT-PCP axis contributes to the motility and invasiveness of both non-transformed and transformed breast cells, and to unravel a novel molecular mechanism contributing to the suppression of the PCP pathway. We hypothesize that EMT inducers engage the Vangl-dependent planar cell polarity pathway to promote the motility and invasiveness of both non-transformed and transformed breast epithelial cells, and to promote breast cancer metastasis. Aim 1 will first examine the extent to which EMT induction in breast cells regulates components of the PCP pathway, and then assess whether key components of the PCP pathway are required for EMT- induced breast cell motility and invasiveness. A subset of Aim 1 studies will also attempt to discern whether PCP signaling regulates EMT. Aim 2 will examine a novel PCP negative regulatory mechanism in detail, exploring the hypothesis that the Vangl-associated E3 ubiquitin ligase Nrdp1 suppresses PCP signaling by mediating the K63 polyubiquitination of Dvl family proteins in breast epithelial and cancer cells. Aim 3 will examine whether the core PCP component Vangl2 contributes to breast cancer metastasis using genetically- engineered and orthotopic transplant mouse models of basal breast cancer. The successful completion of these studies will uncover a novel connection between two developmental programs that are reactivated by tumor cells in promoting malignancy, and will assess the contribution of this synergistic interaction in promoting breast cancer malignancy.