在中国乳腺癌发病率的激增意味着蛋白质翻译后修饰、运输、和分布改变或表观遗传等非遗传因素可能是乳腺癌发生发展的重要机制。在三阴性乳腺癌细胞中，我们发现STAT3具有不同的修饰并形成多种蛋白小体。其中,SEC15依赖的STAT3蛋白小体通过分泌促进三阴性乳腺癌干细胞生长。在此我们提出假说：肿瘤细胞分泌STAT3蛋白小体形成特殊肿瘤干细胞微环境，激活信号通路、维持肿瘤干细胞自我更新、转移及抗药等干性生长。围绕这一假说,我们将运用免疫质谱联仪、新建基因敲除动物模型及蛋白质结构基础的药物设计等手段1)阐明SEC15-STAT3蛋白小体形成和跨膜之机理;2)揭示SEC15-STAT3胞外小体在乳腺癌干细胞所激活信号通路;3)探索SEC15-STAT3胞外小体对乳腺癌干细胞的生长转移复发干性调节及抑制STAT3胞外小体对乳腺癌的干预。为蛋白小体组学新概念、异质性三阴性乳腺癌新机理和治疗新方案提供依据。

Breast cancer incidence increases markedly increased over the past years in China, suggesting non-genetic factors such as aberrant protein post-translational modifications or protein subcellular localization changes or epigenetic factors can be important mechanisms for breast cancer initiation and development. In triple negative breast cancer (TNBC) cells with metastatic property, cytokine activated STAT3 proteins bear multiple posttranslational modifications, leading to the formation of various STAT3 micro-vesicles or endosomes. Surprisingly, SEC15-dependent STAT3 microvesicle secretion rather than nuclear translocation maintains TNBC cell metastatic self-renewal growth property. Inasmuch, we hypothesize that STAT3's tumorigenecity and tumor cell stem properties depend on STAT3 activity in micro-vesicle formation and secretion, and, secreted SEC15-STAT3 microvesicle or exosome serves as an important niche for triggering intracellular signaling pathways for breast cancer stem cell metastatic self-renewal growth. To prove this hypothesis, we will apply mass spectrometry, transgenic mouse model, protein-based drug design and other approaches to 1) explore the mechanisms of SEC15-STAT3 microvesicle formation and cell membrane crossing in TNBC cells; 2) delineate signal transduction initiation by SEC15-STAT3 exosome in TNBC cells, and 3) explore SEC15-STAT3 exosome in maintaining stem properties including self-renew growth, metastasis, and drug-resistance of TNBC stem cells. Our research will provide the clue for the novel concept of protein microvesicleomics，novel mechanism of TNBC breast cancer heterogeneity, as well as new therapy.