circSLCO1B3在三阴乳腺癌脑转移中的作用及其机制

三阴型乳腺癌在乳腺癌分子亚型中脑转移发生率最高。申请者曾研究发现circRNA在三阴乳腺癌生长与肺转移中具有重要调控作用（第一/通讯作者Mol Cancer，Theranostics等），但与脑转移的作用与机制尚不清。申请者预实验发现circSLCO1B3在三阴乳腺癌细胞和脑转移组织中表达下调，甲基化酶抑制剂上调其表达，进一步发现circSLCO1B3抑制肿瘤细胞侵袭转移和类器官增殖，上调P53和PTEN蛋白的表达。由此提出科学假说：circSLCO1B3启动子高甲基化，导致其表达下调，减少P53和miRNAs对PTEN的调控作用，进而促进三阴乳腺癌脑转移。本研究将通过Co-IP、类器官和PDX等技术探讨circSLCO1B3在三阴乳腺癌脑转移中的定植和生长作用，阐明circSLCO1B3启动子甲基化调控机制及其临床意义。本项目的实施将为circRNA在三阴乳腺癌脑转移中提供新的理论依据。

In breast cancer, the incidence of brain metastasis is the highest in the subtype of triple negative breast cancer (TNBC). Studies of the applicant have confirmed that circRNAs play a crucial role of regulation in the tumorigenesis and lung metastasis of TNBC (the first/corresponding authors Mol Cancer，Theranostics etc.). However, the function and mechanism of circRNAs in brain metastasis of TNBC are unclear. In the preliminary experiments, the applicants found that circSLCO1B3 was down-regulated in TNBC cells and brain metastasis tissues, besides, its expression was up-regulated by methylase inhibitors. Furthermore, circSLCO1B3 was found to inhibit the invasion and metastasis of tumor cells, proliferation of patient-derived organoids, and up-regulated the expression of P53 and PTEN proteins. Therefore, a scientific hypothesis is put forward: the hypermethylation of circSLCO1B3 promoter leads to its down-regulated expression, alleviate the regulatory effect of P53 and miRNAs on PTEN, by which promotes the brain metastasis of TNBC. In this project, Co-IP, patient-derived organoids and PDX will be applied to exploring the role of circSLCO1B3 in the brain metastasis of TNBC, elucidating the regulation mechanism of methylation of circSLCO1B3 promoter, and then clarifying its clinical significance. The implementation of this project will provide a new theoretical basis for circRNAs in brain metastasis of TNBC.