先锋转录因子FOXA1通过诱导染色质结构开放，在乳腺癌发生发展中起到重要作用。本研究将针对FOXA1的O-GlcNAc糖基化，1）分析糖基化FOXA1对乳腺癌细胞侵袭-转移潜能的影响；2）通过蛋白质谱，比较野生型和O-GlcNAc位点突变型FOXA1与转录共调节蛋白互作谱的变化，发现新的与乳腺癌转移相关FOXA1互作蛋白；3）通过ChIP-Seq法，在全基因组水平系统分析O-GlcNAc糖基化对FOXA1转录调节活性及下游靶基因转录的影响，发现新的乳腺癌转移相关FOXA1靶基因；4）联合生物信息学分析，揭示O-GlcNAc糖基化的FOXA1调控乳腺癌细胞转移的新机制；5）通过干预FOXA1异常的O-GlcNAc糖基化，体内、体外抑制乳腺癌细胞转移。本研究旨在系统解析FOXA1的O-GlcNAc糖基化重塑细胞侵袭-转移表型的作用机制，为乳腺癌转移治疗提供潜在的防治新靶点和新策略。

FOXA1 is a pioneer factor that contributes to chromatin opening and allows subsequent binding of other transcription factors. Evidence has shown that FOXA1 is essential for almost all estrogen receptor binding events and plays an important role in the genesis and development of breast cancer. However, our understanding of FOXA1 activity regulation is limited. The objective of this study is to explore the mechanisms of FOXA1 O-GlcNAcylation in regulating invasion and metastasis of human breast cancer cells. 1) O-GlcNAc modification site of FOXA1 in breast cancer cells will be identified firstly. The involvement of O-GlcNAcylated FOXA1 in the invasion-metastasis process of breast cancer cells will be confirmed. 2) Mass spectrometry will be used to compare the interaction profiles of wild-type and O-GlcNAc sites mutant FOXA1 with co-regulatory factors, and the metastasis related new FOXA1 co-regulatory factors will be identified. 3) Using ChIP-Seq, the effects of O-GlcNAc modification on FOXA1 transcriptional regulatory activity and downstream target genes transcription will be systematically analyzed on a global scale. The metastasis related novel FOXA1 target genes will be found. 4) Together with bioinformatics analyses further, the mechanism of O-GlcNAc modification of FOXA1 in remodeling invasion-metastasis phenotype of breast cancer cells will be approached. 5) To reverse the invasion and metastasis of breast cancer cells in vitro and in vivo, the abnormal O-GlcNAcylation will be intervened. This research will contribute to develop a comprehensive and systematical mechanism of which O-GlcNAcylated FOXA1 regulates breast cancer cells invasion and metastasis. This study will also provide potential new targets and strategies for breast cancer metastasis prevention.