乳腺癌他莫昔芬耐药中YAP/SRSF9/miR-186-3p/EREG信号轴调控有氧糖酵解的机制研究

乳腺癌中约70%是雌激素受体阳性的Luminal亚型，他莫昔芬为ER+乳腺癌患者内分泌治疗的常用药物。他莫昔芬耐药的乳腺癌患者较易发生骨转移。本课题组前期研究发现EREG/EGFR信号途径调控有氧糖酵解过程，从而促进乳腺癌他莫昔芬耐药及骨转移；并发现miR-186-3p直接下调EREG表达，而SRSF9可通过剪切加工机制抑制miR-186-3p的表达成熟；YAP/TEAD复合物则在SRSF9启动子区域介导转录调控。本项目拟在体外和体内模型中深入探讨YAP/SRSF9/miR-186-3p/EREG信号轴对乳腺癌的有氧糖酵解、他莫昔芬耐药以及骨转移的作用机制，解析SRSF9结合miR-186-3p以及YAP/TEAD结合SRSF9启动子的作用模式，以拓展Hippo与EGFR信号通路交互调控的认识，加深对乳腺癌他莫昔芬耐药和骨转移背后共同效应网络的理解，为乳腺癌新型治疗靶点的发现提供理论基础。

Estrogen receptor positive (ER+) luminal subtype accounts for approximately 70% of breast cancer. Tamoxifen is often used as an endocrine therapy for ER + patients. In clinical practice, it is found that patients with tamoxifen-resistant breast cancer are more prone to bone metastasis. Current studies indicate that epidermal growth factor receptor (EGFR) can promote the colonization, growth and proliferation, angiogenesis, invasion and metastasis of breast cancer cells in the bone microenvironment. While its mechanism remains to be further explored. Our team found that the EREG / EGFR signaling pathway promoted tamoxifen resistance and bone metastasis via regulating the aerobic glycolysis process in breast cancer. Then we found that miR-186-3p down-regulated EREG expression and SRSF9 inhibited miR-186-3p maturation. Besides the transcription of SRSF9 were regulated by the YAP / TEAD complex. While the specific mechanism of YAP / TEAD complex in regulating tamoxifen resistance and bone metastasis in breast cancer remains unknown. This project intends to investigate the effects of YAP / SRSF9 / miR-186-3p / EREG signal axis on aerobic glycolysis, tamoxifen resistance and bone metastasis of breast cancer, to explore the binding site between the SRSF9 and miR-186-3p aswell as the binding site between YAP/TEAD and the promoter of SRSF9. Hoping to pave the theoretic ground for the discovery of new therapeutic targets for breast cancer.