靶向BCL6-TRIB3相互作用抑制乳腺癌干性及转移的分子机制

尽管乳腺癌患者经现代医疗手段治疗后存活率大幅提高，但目前乳腺癌复发仍为困扰肿瘤治疗的重大难题。90%死亡患者均由肿瘤转移造成。乳腺肿瘤干细胞（CSCs）可能是放疗、化疗失败及肿瘤复发的关键原因。目前尚未阐明CSCs功能与微环境组织交互影响等问题的分子机制。前期研究发现，BCL6与乳腺癌发生、复发及干性密切相关；肿瘤微环境富集的应激蛋白TRIB3促进干性因子核内堆积维持肿瘤干性；BCL6-TRIB3相互作用稳定BCL6并阻断BCL6与核辅助抑制子SMRT结合，进而维持肿瘤干性。本项目拟通过乳腺特异性敲除BCL6手段研究自发乳腺癌小鼠肿瘤干性维持及肿瘤发展机制；通过研究BCL6与关键蛋白相互作用，阐明BCL6促进维持肿瘤干性的分子机制，筛选并评价靶向BCL6关键蛋白相互作用的多肽或小分子等先导物。此研究将为抗CSCs药物研发提供理论和实验依据，为乳腺癌转移的临床治疗提供新药靶和新思路。

Although the survival rate of breast cancer patients has been greatly improved after the modern medical treatment, breast recurrence currently is still a major problem for cancer treatment. Breast metastases account for the 90% of cancer-associated deaths. Breast cancer stem cells (CSCs) play essential roles in radiotherapy failure, chemotherapy failure or tumor relapses. However, there is still a lack of research on issues such as the interaction between functions of CSCs and niche microenvironment. Our pilot studies showed high-level BCL6 associates with accelerated breast cancer progression and breast cancer stemness. Our results also indicated that the microenvironment stress condition promotes the high expression of TRIB3 in breast cancer cells, which causes nuclear accumulation of stem factors and promotes cancer stemness. Our proposal aims to investigate the role of BCL6 on breast cancer development, stemness and metastasis by using spontaneous breast animal model. We also intend to clarify the molecular mechanism of BCL6 related protein interaction on breast cancer, and identify the leading peptides or small compounds to target BCL6 related protein-protein interaction. Our study will provide theoretical and experimental evidences for anti-CSCs drug development, and identify new drug targets and novel strategy for anti-metastasis treatment.