类泛素化neddylation修饰通过激活内质网应激通路IRE1/XBP1导致氟维司群耐药的机制研究

乳腺癌内分泌治疗耐药导致患者复发转移甚至死亡，亟待阐明其发生机理，探索新型治疗策略。申请人前期研究发现neddylation通路在乳腺癌中过度活化并提示患者不良预后；靶向neddylation通路可通过抑制雌激素受体转录而提高氟维司群的抗肿瘤效果。基于氟维司群耐药细胞中neddylation通路显著活化，靶向neddylation通路抑制内质网应激通路IRE1/XBP1，我们提出假说：neddylation通路激活IRE1/XBP1通路导致氟维司群耐药。基于此，本项目将系统研究neddylation活化激活IRE1/XBP1通路并导致氟维司群耐药的分子机制，进而评价靶向neddylation通路对氟维司群耐药的改善作用及XBP1对氟维司群耐药的预测作用。本项目的预期成果有助于阐明neddylation通路导致氟维司群耐药的分子机制，为靶向此通路改善氟维司群耐药提供新的科学依据。

Breast cancer endocrine therapy resistance leads to disease recurrence and metastasis even death, which is urgent to clarify its pathogenesis and explore new therapeutic strategies. Our previous study has found that neddylation pathway was overactivated in breast cancer and indicated patients'poorer prognosis. Targeting neddylation inhibited ER transcription and increased the anti-tumor activity of fulvestrant. Based on the finding that neddylation pathway is overactivated in fulvestrant-resistant cells and targeting neddylation pathway inhibits endoplasmic reticulum stress signaling pathway IRE1/XBP1, we hypothesized that neddylation activation lead to fulvestrant resistance via upregulating IRE1/XBP1 pathway.To test this hypothesis, the project will systematically investigate the mechanism of IRE1/XBP1 pathway activation by neddylation and the the mechanism of fulvestrant resistance. Furthermore, to evaluate the improvement of fulvestrant resistance by neddyaltion pathway blocking and the prognostic value of XBP1 for fulvestrant resistance. The desired results of this study will help to clarify the molecular mechanism of fulvestrant resistance caused by neddylation pathway activation, and provide scientific basis for the treatment of fulvestrant resistance.