Planar cell polarity pathway contribution to breast cancer metastasis

平面细胞极性（PCP）途径通过介导细胞内的细胞周期调控，在胚胎发育中起着重要作用。 运动事件所需的适当组织结构。越来越多的证据表明，五氯苯酚的途径是 被一些实体瘤利用以促进它们的侵袭性和转移潜力。同样，上皮细胞- 间充质转化（EMT）是在发育期间广泛参与的细胞程序， 它们的上皮特征，包括顶端-基底极性和细胞-细胞相互作用，并获得迁移性， 具有侵袭性的特性，以呈现更多的间充质干细胞性质。众所周知，实体瘤细胞 使EMT参与转移的启动。拟议研究的目的是检查一种分子 水平这两个发展途径之间的联系，以辨别EMT-PCP轴 有助于非转化和转化乳腺细胞的运动性和侵袭性， 揭示了一种新的分子机制，有助于抑制PCP途径。我们假设 EMT诱导剂参与Vangl依赖性平面细胞极性途径以促进运动性， 非转化和转化乳腺上皮细胞的侵袭性，并促进乳腺癌 转移目的1将首先检查乳腺细胞中EMT诱导调节乳腺癌细胞中EMT组分的程度。 五氯苯酚途径，然后评估五氯苯酚途径的关键组成部分是否是EMT所必需的- 诱导乳腺细胞的运动性和侵袭性。目标1研究的一个子集也将试图辨别 PCP信号调节EMT。目的2将详细研究一种新的PCP负调控机制， 探索Vangl相关的E3泛素连接酶Nrdp 1通过以下途径抑制PCP信号传导的假设： 介导乳腺上皮细胞和癌细胞中Dvl家族蛋白的K63多聚泛素化。目标3将 使用遗传学方法检查PCP的核心成分Vangl 2是否有助于乳腺癌转移。 基底乳腺癌的工程化和原位移植小鼠模型。圆满完成 这些研究将揭示两种发育程序之间的新联系， 肿瘤细胞在促进恶性肿瘤，并将评估这种协同作用的贡献，促进 乳腺癌恶性肿瘤。

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.