OSR1调控内质网应激PERK/ATF4通路在三阴性乳腺癌脑转移中的作用及机制研究

三阴性乳腺癌（TNBC）脑转移具有发病早，恶性度高的特点，其发生机制不明。前期研究发现，活化的氧化应激反应激酶1（OSR1）在TNBC脑转移组织中表达显著增加，在我们筛选出的TNBC脑转移细胞株中也发现有高表达，抑制OSR1活性可明显降低其转移能力，提示OSR1可能参与TNBC脑转移。进一步研究表明，OSR1选择性激活内质网应激PERK/ATF4通路，促进基质蛋白POSTN和THBS1分泌，继而影响血脑屏障紧密连接完整性，下调上述基质蛋白可抑制TNBC脑转移细胞跨体外血脑屏障迁移。基于此，本项目拟探讨：①明确OSR1信号通路在TNBC脑转移中的作用；②揭示OSR1介导的内质网应激-基质蛋白信号通路调控机制以及对TNBC脑转移的影响；③干预OSR1及相关分子功能，观察是否能抑制TNBC脑转移。本项目结果将有助于阐明TNBC脑转移新机制，为其靶向治疗提供新靶点。

Triple-negative breast cancer (TNBC) has the propensity to progress aggressively and early metastasize to the brain. However, its mechanism is unknown. Our previous study found that the expression of activated oxidative stress responsive kinase 1 (OSR1) was significantly increased in the TNBC brain metastasis tissues and screened TNBC brain metastasis cell lines. Downregulating OSR1 can inhibit the metastasis of TNBC brain metastasis cells. We speculate that OSR1 may be closely related to the occurrence of TNBC brain metastasis. Further research showed that OSR1 could selectively activate endoplasmic reticulum stress (ERS) PERK/ATF4 signaling and promote the secretion of matrix proteins periostin (POSTN) and thrombospondin 1 (THBS1), which affect the integrity of the tight junction of the blood-brain barrier. Deleting these matrix proteins inhibited the migration of TNBC brain metastasis cells across the blood-brain barrier in vitro. Based on these results, this project will further analyze the role of OSR1 signaling in TNBC brain metastasis and investigate how OSR1-mediated ERS signaling regulates the expression of matrix proteins and its effect on brain metastasis of TNBC. Finally, we try to intervene in the function of OSR1 and related molecules to observe whether it can inhibit TNBC brain metastasis. The results of this project will help to elucidate the new mechanisms of TNBC brain metastasis and provide new drug targets for brain metastasis therapy.