高度的侵袭转移性是TNBC预后差的重要原因之一。前期发现Claudin4低表达与TNBC患者的淋巴结转移正相关；RNA-seq筛选出Claudin4-Low型TNBC中circEFEMP1显著增高，与PRC2亚基直接结合并介导HOXA6启动子区H3K27me3修饰；HOXA6分别与Claudin4、ERα和PR的启动子区结合。推测circEFEMP1招募PRC2促进HOXA6启动子区组蛋白甲基化修饰调控Claudin4-Low型TNBC迁移侵袭和转移。项目拟研究circEFEMP1招募并结合PRC2亚基EZH2；PRC2/EZH2介导HOXA6启动子区的H3K27me3修饰；HOXA6促进Claudin4、ERα和PR的转录，调控Claudin4-Low型TNBC细胞迁移侵袭的作用机制；通过裸鼠移植瘤模型，验证上述机制；收集临床病例，研究上述靶分子临床意义。项目将为TNBC诊治提供依据。

High frequency of invasion and metastasis is one of the most important reasons for the poor prognosis of TNBC. It was found that the low expression of Claudin4 was significantly correlated with lymph node metastasis in TNBC patients. By RNA-seq screening of Claudin4-Low TNBC circEFEMP1 was demonstrated significantly upregulated and directly bound to EZH2 subunit of PRC2, which mediated the modification of H3K27me3 in HOXA6 promoter region. HOXA6 binds to the promoters of Claudin4, ERα, and PR, respectively. It was speculated that circEFEMP1 recruiting PRC2 promoted histone methylation of specific HOXA6 promoter region to regulate the invasion, migration and metastasis in Claudin4-Low TNBC tumors. The project is designed to study the underlying mechanism of the recruitment of PRC2 subunit EZH2 to circEFEMP1, the modification of H3K27me3 mediated by PRC2/EZH2 in HOXA6 promoter region, the transcription of HOXA6 on Claudin4, ERα, and PR, and regulation of invasion and migration in Claudin4-Low TNBC. The mechanism was verified by xenograft nude mice model. Clinical data was collected to study the clinical significance of the above targets. The project will provide new basis for TNBC diagnosis and treatment.