细胞周期激酶Aurora-A激活MAPK/mTOR信号通路促进三阴乳腺癌转移的机制研究

Triple negative breast cancer manifests high metastasis and recurrence, emerging as a major challenge for the treatment of breast cancer. We showed that Aur-A is overexpressed in triple negative breast cancer cell lines and tumor tissues, leading to tumor progression (Plos one, 2013). However, how Aur-A mediates the metastasis of triple negative breast cancer remains unknown. mTOR pathway has been shown to be overexpressed in triple negative breast cancer. Recently, we have shown that Aur-A can inhibit autophagy by activating mTOR via a PI3K/Akt-independent way (Autophagy, 2012). MAPK is the other crucial way to activate mTOR, and we propose that Aur-A may activate MAPK/mTOR pathway to promote the metastasis of triple negative breast cancer. We plan to establish an Aur-A-induced metastatic cell model in triple negative breast cancer cells, and investigate the mechanism of how Aur-A promotes metastasis by activating MAPK/mTOR pathway, and clarify the feasibility to reverse metastasis by targeting Aur-A and mTOR. By using an animal model, we continue to confirm the feasibility that reversing metastasis by double targeting Aur-A and mTOR and its relationship with therapeutic effects and prognosis. Our present proposal will identify a new metastasis mechanism of triple negative breast cancer, and provide scientific evidence that Aur-A and mTOR serve as double targets for triple negative breast cancer treatment.

三阴乳腺癌因其高转移及易复发的特性成为乳腺癌治疗的难点。申请人发现Aur-A激酶在三阴乳腺癌细胞及组织中高表达并促进肿瘤进展(Plos one,2013)。但是，Aur-A如何介导三阴乳腺癌转移尚不清楚。mTOR在三阴乳腺癌中高表达已见报道。我们近期发现，Aur-A以不依赖PI3K/Akt的方式激活mTOR抑制自噬(Autophagy,2012)。MAPK通路是激活mTOR的另一条重要路径，我们提出Aur-A激活MAPK/mTOR促进三阴乳腺癌转移的可能性。本课题拟构建Aur-A促进三阴乳腺癌转移的细胞模型，研究其激活MAPK/mTOR促进转移的机制，阐明干预Aur-A及mTOR逆转该转移的可行性；并在动物模型中验证联合靶向Aur-A及mTOR逆转转移与肿瘤治疗及预后的关系。本课题有望揭示三阴乳腺癌转移的新机制，为确立Aur-A及mTOR作为三阴乳腺癌治疗的双靶点提供更充分的科学依据。

三阴乳腺癌（triple negative breast cancer, TNBC）作为乳腺癌的一个特殊类型表现为雌激素受体（Estrogen receptor，ER），孕激素受体（Progesterone receptors，PR）与人类表皮生长因子受体2（Human epidermal growth factor receptor 2，HER2）均呈阴性。因其高侵袭性的肿瘤学特性及对现有的内分泌及分子靶向治疗无明显疗效而较其他类型乳腺癌的预后明显差，从而成为乳腺癌治疗领域的一个难点。我们之前的研究表明有丝分裂丝氨酸/苏氨酸极光激酶家族的成员Aur-A激酶，在TNBC细胞和组织中过度表达并与肿瘤增殖和不良预后相关。但是具体调控机制还不清楚。在这项研究中，我们首先检测了Aur-A和mTOR在乳腺癌细胞和组织中的表达，发现Aur-A和mTOR在TNBC细胞系和人类组织中呈正相关。 抑制Aur-A的活性或敲除Aur-A蛋白均可抑制p-mTOR的表达，而Aur-A的过度表达可增加p-mTOR的表达。此外，Aur-A的过度表达促进了细胞增殖和迁移，同时敲除mTOR或抑制mTOR活性均可逆转这一现象。我们接下来证明Aur-A通过MAPK途径正向调节mTOR活性。最后，我们发现Aur-A和mTOR的双重抑制在TNBC体外和体内显示出显着的协同效应，表明两种靶向Aur-A和mTOR的抑制剂的组合可以作为TNBC潜在的治疗策略。