应激蛋白TRIB3维持乳腺干细胞与肿瘤干细胞的差异特性及药靶鉴定

乳腺癌是威胁世界女性健康的头号杀手，虽然目前临床治疗提高了患者的生存率，但肿瘤的复发、转移、耐药仍是困扰乳腺癌治疗的首要难题。肿瘤干细胞（CSCs）是导致肿瘤耐药、复发后转移的根本原因。目前尚未完全阐明CSCs及与正常乳腺干细胞的差异特征，限制了靶向CSCs治疗的药物研发。申报人前期研究发现：正常微环境中，TRIB3通过维持乳腺导管干细胞（LP）维持乳腺发育；肿瘤微环境中，TRIB3维持LP功能失调，上调CD24hiCD90hi的CSCs促进乳腺癌进程。本项目拟通过TRIB3-mCherry、乳腺敲除TRIB3等手段，阐明导致TRIB3维持LP功能失调，促进乳腺癌进程的关键蛋白；筛选与评价靶向关键蛋白的先导物，通过恢复TRIB3维持乳腺发育，抑制乳腺癌发生发展及转移的功能。此研究将为特异性靶向CSCs的先导物发现提供理论依据与数据支持，为乳腺癌复发转移及耐药的临床治疗提供新药靶和新

Breast cancer is the first threat to the world's female health. Although the current clinical treatment has improved the survival rate of patients, the recurrence, metastasis, drug resistance of tumors is still the primary problem that hampers breast cancer treatment. Cancer stem cells (CSCs) are the essential reasons for tumor resistance and metastasis. It is not clear for the origin of CSCs and the difference between CSCs and mammal stem cells, which limited the targeted therapy for CSCs. We have found that TRIB3 maintained breast development by maintaining Luminal mammary progenitor (LP) in normal microenvironments. TRIB3 maintained LP dysfunction and promoted breast cancer progression through increasing the CSCs population in the tumor microenvironment. The project aim is to clarify the essential proteins that lead to TRIB3 maintenance LP dysfunction and promote breast cancer progress by using TRIB3-mCherry and Trib3-KO animal model. To screen and evaluate the inhibition of breast cancer progression by precursors. This study will provide a theoretical basis and data support for drug development that are resistant to CSCs without harming normal breast stem cells. Furthermore, it provides new drug targets and new ideas for the clinical treatment of breast cancer recurrence, metastasis, and drug resistance.