BAG3对乳腺肿瘤干细胞的影响及自噬在其中的作用

肿瘤干细胞（CSC）在肿瘤发生、发展和转移中发挥重要作用，是肿瘤复发的根源。BAG3是多功能蛋白，具有调控细胞增殖、凋亡、迁移、侵袭、自噬等功能。最近我们发现BAG3在乳腺肿瘤组织中高表达，并且影响MCF7细胞中乳腺肿瘤干细胞（BCSC）标志分子的表达及球囊形成率，提示BAG3具有调控BCSC的新功能。研究表明自噬对BCSC等肿瘤干细胞的自我更新至关重要，而在包括乳腺癌等许多肿瘤中BECN1基因缺失或变异，表明CSC中的自噬可能为BECN1非依赖性，即非经典自噬。最近我们报道了BAG3在BECN1非依赖性自噬中发挥关键作用。因此我们推测BAG3通过自噬调控BCSC，并且已初步证实BAG3增加球囊细胞自噬水平。本项目拟在前期工作基础上，阐明BAG3对BCSC自我更新和“干性”维持的影响及自噬在其中的作用。该项目有助于我们深入了解乳腺癌的生物学特性，有利于寻求针对BCSC靶向治疗的新疗法。

Cancer stem cells (CSC) play critical roles in tumorigenesis, progression and metastasis, which are considered as the root cause for cancer recurrence. BAG3 is involved in a number of cellular processes including cell proliferation, apoptosis, adhesion, invasion, migration and autophagy. Recently we demonstrated that human breast cancer tissues expresse high level of BAG3 compared with their peripheral normal tissues. In addition, we found that BAG3 affected the expression of surface markers of breast cancer stem cells (BCSC), as well as mammosphere-forming capacities of MCF7 cells implying a novel function of BAG3 in regulation of BCSC. Very recently it has been reported that autophagy plays a critical in stemness maintenance of CSC including BCSC. Coupled with the fact that BECN1 gene is deleted or mutated in various tumors including breast cancer, we suppose that autophagy occurred in BCSC might be BECN1-independent autophagy, namely noncanonical autophagy. Recently we have reported that BAG3 plays a critical role in BECN1-independent autophagy. Therefore, we hypothesize that BAG3 might affect BCSC via autophagy. The primary result that BAG3 enhanced autophagy in mammospheres of MCF7 cells supported our hypothesis. Based on these previous data, the current project aims to clarify the influence of BAG3 on the self-renewal and stemness maintenance of BCSC, as well as the role of autophagy on it. This project will shed light on biological and molecular features of breast cancers, provide novel potential targets to eradicate BCSC in breast cancer.