靶向BCL6-TRIB3相互作用抑制乳腺癌干性及转移的分子机制

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.

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。

肿瘤干细胞尤其是肿瘤休眠干细胞的存在是引起肿瘤治疗失败、肿瘤转移及复发的关键原因。肿瘤微环境是肿瘤干细胞的土壤，放化疗导致肿瘤干性增强，都是导致肿瘤复发转移、耐药的重要原因，也是目前肿瘤干细胞治疗的难题。因此靶向肿瘤微环境及放化疗富集的肿瘤干细胞有望成为新的治疗策略。本项目研究发现肿瘤微环境条件下，乳腺肿瘤细胞高表达TRIB3通过与AKT相互作用，激活FOXO1-SOX2正反馈环路，促进肿瘤干性；靶向TRIB3/AKT相互作用的先导肽Pep2-Ae，阻断肿瘤微环境与肿瘤干细胞的交互调节。关注放化疗后肿瘤干性变化，结果发现放化疗后的乳腺肿瘤细胞高表达BCL6；该核因子结合超级增强子及启动子进而抑制SH3RF2介导的RAD51蛋白质降解，促进DNA修复功能，增强肿瘤干性；BCL6/TRIB3相互作用抑制BCL6蛋白质降解，同时高表达BCL6与TRIB3的临床乳腺癌患者复发率极高；靶向BCL6/TRIB3相互作用的先导肽TB4抑制放化疗导致乳腺肿瘤干性增强。关注核因子BCL6和应激蛋白TRIB3促进增加的干性因子，结果发现IL-17A在急性淋巴细胞白血病骨髓微环境的干性维持中发挥重要作用，这为自主研发的人源抗IL17A抗体拓展新的适应症。综上，本研究阐明TRIB3/AKT相互作用在肿瘤干性微环境发挥关键作用的机制，可能为联用AKT抑制剂临床应用提供理论基础；阐释放化疗后肿瘤干性增强的机制，结果发现放化疗增强的BCL6促进DNA修复并促进肿瘤干性，靶向TRIB3/BCL6相互作用加速BCL6降解能够抑制肿瘤干性增强。筛选获得的靶向TRIB3/AKT、TRIB3/BCL6、TRIB3/GSK3 bteta等相互作用多肽先导物以及抗IL-17A抗体为开发抑制肿瘤干性的抗肿瘤药提供理论基础和物质准备。项目执行期间发表论文7篇，申请专利5项，参加学术会议并做会议报告8次，培养研究生9名。

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