慢性心理应激激活AngII-AT1R途径促进乳腺癌进展及GABARAP调节机制

Abnormal hormone secretion caused by chronic psychological stress is an important cause of breast cancer progression.However,the role of angiotensin II (AngII) on chronic psychological stress is unknown.Our previous research has confirmed that angiotensin II binds to angiotensin II receptor 1 (AngII-AT1R) may contribute to theprogression of breast cancer.The preliminary study found that AngII、AT1R and GABARAP of chronic psychological stress group increased significantly in breast cancer xenograft ,GABARAP binds to and promotes trafficking of the AT1R to the plasma membrane.So we hypothesized that chronic psychological stress may activates AngII-AT1R pathway regulated GABARAP to promote progression of breast cancer.This project aims to observe the proliferation,apoptosis,invasion,and downstream pathways by regulating of AngII/AT1R in vitro and restraint stress of nude mice;observe the relationship between AngII/AT1R/GABARAP expression and patients psychological state and prognosis in human breast cancer.Meanwhile, we observe the role of AT1R assosiated protein GABARAP on AngII-AT1R pathway.This study wall provide the evidence for the application of AT1R inhibitors for breast cancer progression caused by chronic psychological stress.

慢性心理应激相关激素异常分泌是乳腺癌进展的重要原因，应激激素血管紧张素II的作用不明。课题组证实血管紧张素II通过血管紧张素II受体1（AngII-AT1R）促进乳腺癌进展 (Cancer Letters 2013，国自然 81573001)。前期研究在人乳腺癌裸鼠原位移植瘤中慢性心理应激组AngII、AT1R及相关蛋白GABARAP表达升高；在乳腺癌组织中GABARAP表达和AT1R正相关并促进AT1R转运至细胞膜。我们推测慢性心理应激激活AngII-AT1R途径促进乳腺癌进展并且受GABARAP正向调节。本项目拟在体外实验、束缚应激裸鼠移植瘤中分别干预AngII/AT1R及GABARAP表达观察对乳腺癌增殖、凋亡、侵袭及下游通路的影响，分析人乳腺癌组织AngII/AT1R/GABARAP表达与患者心理状态及预后的关系。为AT1R抑制剂用于克服慢性心理应激所致的乳腺癌进展提供依据。

慢性心理应激相关激素异常分泌是乳腺癌进展的重要原因，应激激素血管紧张素II的作用不明。本项目拟在体外实验、束缚应激裸鼠移植瘤中分别干预AngII/AT1及GABARAP表达观察对乳腺癌增殖、凋亡、侵袭及下游通路的影响，分析人乳腺癌组织AngII/AT1/GABARAP表达与患者心理状态及预后的关系。为AT1R抑制剂用于克服慢性心理应激所致的乳腺癌进展提供依据。课题组证实慢性心理应激乳腺癌患者血浆Ang II水平、组织局部Ang II水平表达均高于非应激乳腺癌患者组。慢性应激可以激活Ang II-AT1途径进而通过下游FN1分子激活FAK/SRC通路。GABARAP 在乳腺癌组织中较正常乳腺组织低表达，低表达GABARAP 的乳腺癌患者较高表达者预后差。GABARAP 通过影响 EMT 抑制乳腺癌的侵袭和转移。GABARAP 通过抑制AKT/mTOR 通路调控乳腺癌的侵袭和转移。