唐氏综合症病人患乳癌几率低于常人，其原因与多出的染色体上表达钙调磷酸酶调节蛋白（RCAN1）相关。但RCAN1在乳腺癌中的表达调控和功能尙不清楚。我们发现RCAN1.4在乳腺癌组织中表达下调且患者预后差；过表达该基因抑制乳腺癌细胞成瘤侵袭迁移能力，下调NFAT下游靶基因表达；发现该基因启动子下游存在调控其表达的远端超级增强子。本课题拟在已建立的转基因小鼠模型上研究RCAN1.4敲除对小鼠乳腺癌发生发展的影响；研究其缺失后通过激活CaN（钙调神经磷酸酶）/NFAT通路对乳腺癌细胞恶性进展及上皮细胞恶性转化的影响；明确超级增强子对其表达和生物学功能的调控作用；阐明由于转录因子RUNX3在乳腺癌中低表达，致使调控RCAN1.4的超级增强子驱动异常，导致其表达减少的机制；在转基因鼠、PDX等模型上，探讨钙调磷酸酶抑制剂或过表达RCAN1.4能否增强乳腺癌细胞对化疗的敏感性，为乳腺癌治疗提供新思路。

The risk of breast cancer in patients with Down's syndrome is significantly lower than that in normal people, which is related to excessive Regulator of Calcineurin 1 (RCAN1) encoded by excessive chromosome 21. However, the expression and significance of RCAN1 in breast cancer are still unclear. In our preliminary study, we found that RCAN 1.4 expression is an independent prognostic factor for breast cancer that’s down-regulated in breast cancer tissues. Low expression of RCAN 1.4 was associated with poor prognosis. Overexpression of RCAN 1.4 inhibited proliferation, migration and invasion of breast cancer cells, and up-regulated the expression of downstream genes of CaN (calcineurin) / NFAT pathway. Further studies revealed that there might be a distal super-enhancer located \ the downstream of core promoter of RCAN1.4. that can regulate the expression of RCAN1.4. And RUNX3, a transcription factor, might play a important role in the abnormal expression of RCAN1.4 in breast cancer driven by super-enhancer. In this proposal, we will use the established RCAN 1.4 loxp/loxpCre+/+MMTV-PyMT(+) mice model to study the effect of RCAN 1.4 knockout on the occurrence and development of breast cancer in mice.We will explore the effect of RCAN 1.4 on the tumorigenesis and malignant transformation of breast cancer cell lines and MCF-10A through CaN/NFAT signaling pathway will also be studied. By using CHIP-seq, ATAC-seq, double-CRISPR, 3C-q PCR and other techniques, we will also investigate the epigenetic modification map of RCAN 1.4, and the interaction between RCAN 1.4 promoter and super-enhancer region, and the regulatory role of super-enhancer on the expression and biological function RCAN 1.4. We will also clarified the mechanism that the down-regulation of RCAN1.4 caused by low expression of RUNX3 through disturbing the driving function of super-enhancer of RCAN1.4 in breast cancer. Finally, we will use RCAN 1.4 loxp/loxpCre+/+MMTV-PyMT(+) mice, PDX model of breast cancer and breast cancer xenografts in nude mice to explore whether calcineurin inhibitors or overexpression of RCAN 1.4 can enhance the chemosensitivity to breast cancer cells. This study will provide new prospects for the treatment of breast cancer patients with low expression of RCAN 1.4.