转录因子FOXA2调控乳腺癌细胞上皮间质转化的分子机制研究

项目名称： 转录因子FOXA2调控乳腺癌细胞上皮间质转化的分子机制研究

项目编号： No.81472718

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 谭拥军

作者单位： 湖南大学

项目金额： 75万元

中文摘要： 乳腺癌转移是临床治疗中的一大难题。乳腺癌细胞发生上皮间质转化（EMT）是导致转移的早期事件, 基因表达调控在其中发挥了关键作用。研究特定转录因子调节乳腺癌细胞EMT的分子机理，对阐明肿瘤转移机制和临床治疗中应对乳腺癌转移具有重要意义。前期工作表明，转录因子FOXA2是乳腺癌细胞EMT过程中的关键抑制因子。本项目将以FOXA2为研究对象，运用乳腺癌E型MCF-7细胞和M型MDA-MB-231细胞为EMT对应细胞模型，确认EMT过程中FOXA2的互作蛋白，探讨乳腺癌细胞中FOXA2刺激E型基因和抑制M型基因表达的分子作用机制，并在EGF诱导E型MCF-10A细胞发生EMT过程的细胞模型中加以验证。从乳腺癌细胞株及临床样本中分选获得E型和M型细胞亚群，在裸鼠转移模型中研究FOXA2及互作蛋白表达水平与不同亚群细胞迁移能力之间的对应关系，确立将FOXA2用于抑制乳腺癌细胞EMT过程的临床应用价值。

中文关键词： C21_乳腺肿瘤；转录因子FOXA2；上皮间质转化；基因表达调控；表观遗传

英文摘要： To control breast cancer metastasis is a big challenge in the clinical treatment of this malignant tumor. Epithelial-mesenchymal transition (EMT) is considered to play critical roles in the prophase of breast cancer metastasis. It is well known that many genes significantly change in their gene expression during EMT. To study gene regulatory mechanisms of certain transcription factors during breast cancer cell EMT will help us to understand the metastasis of this tumor and to design new therapeutic strategies to treat this disease. Our preliminary data have confirmed that transcription factor FOXA2 is one of the key factors preventing EMT of breast cancer cells. In this proposal, we will continue to focus on the regulatory functions of FOXA2 on gene expression during EMT. We intend to identify co-factors that interact with FOXA2 in breast cell lines MCF-7 (epithelial type) and MDA-MB-231 (mesenchymal type), and test whether the interaction between FOXA2 and its co-factor(s) mediates the stimulation of E-type genes and repression of M-type genes through FOXA2. This hypothesis will be further tested in the EGF-induced EMT model of breast epithelial cell line MCF-10A. We plan to isolate the sub-groups of E-type cells and M-type cells from clinical breast cancer samples by cell sorting. By knocking down FOXA2 levels in E-type cells and elevating FOXA2 levels in M-type cells, we will test whether the levels of FOXA2 in breast cancer cells will affect the tumorigenicity and mobility of different sub-group cells in the nude mouse model of metastasis. We hope that this study will confirm the value of FOXA2 for preventing the EMT of breast cancer cells in clinical therapeutic strategies of breast cancer metastasis treatment.

英文关键词： Breast Cancer;Transcription Factor FOXA2;EMT;Gene Expression Regulation;Epigenetics