靶向干预PKCα- MAP4K4-SASH1磷酸化信号通路阻止三阴型乳腺癌侵袭转移的机制研究

三阴型乳腺癌(TNBC)的侵袭转移是其难以治愈的重要原因，急需发现调控侵袭转移的新的异常翻译后修饰蛋白并对其进行靶向干预。我们前期研究发现了SASH1作为一个新的蛋白激酶，可通过MAP4K4激酶结合PKCα激酶，并被MAP4K4磷酸化修饰。在乳腺细胞株，PKCα的RNAi、激动剂和抑制剂处理等可调节SASH1和MAP4K4的表达变化。小分子化合物Ingenol和GNE-495靶向干预MDA-MB-231细胞PKCα和MAP4K4的表达，阻断PKCα对MAP4K4和SASH1的磷酸化修饰。因此，我们推测一条新的PKCα-MAP4K4-SASH1磷酸化激酶级联可能调节TNBC的侵袭转移，并被Ingenol和GNE-495靶向阻断。我们拟在更多TNBC细胞株和细胞移植瘤模型，分析这两种小分子化合物靶向干预这条级联对TNBC侵袭转移的影响。本研究将为防治TNBC的侵袭转移提供新的策略。

Invasion and metastases of triple negative breast cancer（TNBC）is the main.reason why it is difficult to cure. It is very necessary to find out novel abnormal post-translation modified proteins such as protein kinases acting important roles in the process of Invasion and metastases to be targeted. Our previous investigations indicate that SASH1 acting as a novel protein kinase, binds to PKCα through the associations of SASH1 and MAP4K4 ，and SASH1 is phosphorylated by MAP4K4. In breast cancer cell lines，the treatments including RNAi interference，agonist and inhibitor of PKCα and etc mediate expression of SASH1 and MAP4K4. The small molecular compounds, GNE-495 targeted to MAP4K4 and Ingenol targeted to PKCα in MDA-MB-231 cells, either alone or in combination, block the phosphorylation of MAP4K4 and PKCα，respectively. Therefore, we guess that a novel PKCα -MAP4K4-SASH1 phosphorylation kinase cascade probably mediates invasion and metastases of TNBC and this kinase cascade can be targeted intervention by Ingenol and GNE-495. We will analyze the effects of targeted intervention to the kinase cascade by the two small molecular compounds on invasion and metastases of TNBC in more NBC cells and xenografts models of TNBC cells. This study will provide a novel therapeutic strategy to the treatment of TNBC.