三维模型中Aurora-A异常导致极性破坏在乳腺细胞恶性转化中的作用与机制研究

细胞极性的丢失与破坏是乳腺癌发生与转移过程中的早期关键事件。新近研究发现Aurora-A激酶（Aur-A）在果蝇细胞极性的建立中发挥重要作用。我们的前期研究表明，Aur-A高表达能促进肿瘤的发生、发展(Mol. Cancer, 2009；Cancer Res, 2007；Carcinogenesis, 2008)。本课题组成功构建了模拟体内乳腺癌变过程的三维细胞培养模型，并在此模型中观察到过表达Aur-A导致乳腺上皮细胞极性紊乱、恶性增殖，提示Aur-A引起的极性破坏与细胞癌转化密切相关；且Aur-A能调控极性蛋白aPKC、Scribble的表达，但其机制尚未阐明。本课题旨在研究Aur-A异常是否通过影响极性蛋白（Par，Scribble复合物）表达、定位及其信号通路，破坏细胞极性，最终导致癌转化。再结合动物模型和临床资料分析，阐明Aur-A破坏细胞极性促进乳腺癌发生的分子机制。

The disruption of polarized epithelial organization in epithelial cells plays crucial role during development of carcinoma. Recent studies found that Aur-A was required for asymmetric cell division and generation of polarity in drosophila cells. Previously, we showed that over-expressed Aur-A was associated with cancer progression (Mol. Cancer, 2009；Cancer Res, 2007, 2010；Carcinogenesis, 2008). We have established a three-dimensional (3D) cell culture model that may mimic the cellular transformation in vivo by using real-time confocal microscopy. We found that over-expression of Aur-A induced polarity disruption of 3D cultured breast epithelial cells. Moreover, we showed that Aur-A up-regulated aPKC expression and down-regulated Scribble level. These studies suggested that Aur-A induced disruption of cell polarity may play key role in cell transformation and tumorigenesis. However, the molecular mechanism responsible for polarity disruption has not been identified. In this study, we will study the effect of Aur-A on polarity disruption, proliferation, apoptosis and migration of three-dimensional cultured breast epithelial cells. Moreover, we will detect whether Aur-A disrupts polarity through targeting polarity proteins (Par, Scribble complex) and signaling. Combine with animal model and clinical data analysis, this study will elucidate the molecular mechanism responsible for Aur-A induced polarity disruption in breast cancer progression.