PI3K/AKT/mTOR信号通路介导DNA：RNA异源三聚体（R-LOOP）促进乳腺癌内分泌治疗耐药的分子机制研究

R-LOOP介导的DNA损伤及基因组不稳定是HR阳性乳腺癌内分泌治疗耐药的重要原因之一，但在乳腺癌中调控R-LOOP的机制尚不明确。我们前期研究发现高水平R-LOOP是HR阳性乳腺癌复发及内分泌治疗耐药的分子标记;通过转录组分析发现高水平的R-LOOP与PI3K/Akt/mTOR通路活性和PD-L1高表达成正相关；抑制PI3K通路活性可下调R-LOOP水平。我们推测PI3K/Akt/mTOR通路的过度激活可能诱导R-LOOP累积并介导内分泌治疗耐药。本项目拟进一步明确高R-LOOP水平的HR阳性乳腺癌预后差及内分泌耐药的分子机制；阐明PI3K/Akt/mTOR通路调控R-LOOP水平的分子机理；最后，在高水平R-LOOP临床前模型中探究PI3K通路抑制剂联合R-LOOP及PD-1/L1抑制剂的治疗效果。本项目将为HR+乳腺癌内分泌耐药提供新的机制，为进一步提高内分泌治疗效果提供新的思路。

High level R-LOOP induced DNA damage and genomic instability are the main causes of resistance to endocrine therapy in HR-positive breast cancer. However, the underlying mechanisms of regulation of R-LOOP in HR+ breast cancer is remained unknown. Our pilot studies showed that high level R-LOOP is associated with the recurrence and resistance to endocrine therapy in HR-positive breast cancer. In addition, transcriptome profiling analysis revealed that high level R-LOOP was positively correlated with the aberrant activity of PI3K/Akt/mTOR signaling pathway and up-regulation of PD-L1 expression. Targeted PI3K signaling with PI3K inhibitor led to the down-regulation of R-LOOP. Thus, we proposed that excessive activation of the PI3K/Akt/mTOR signaling pathway upregulates high level R-LOOP and then induces DNA damage effects, leading to the resistance to endocrine therapy. To approve our hypothesis, we will decipher the resistant mechanism of endocrine therapy in hormone receptor-positive breast cancer patients, which mediated by high level R-LOOP. We will further investigate relationship between the PI3K/Akt/mTOR signaling pathway and R-LOOP levels. In addition, we will also exploit the therapeutic effect of PI3K inhibitor combined with R-loop inhibitors and/or- PD-1 / L1 inhibitors in preclinical model of HR+/HER- breast cancer with high level R-LOOP. Taken together, we believe that this study would provide a novel resistant mechanism for endocrine therapy in HR + breast cancer. Importantly, this work may provide a novel therapeutic strategy to improve the efficacy of endocrine therapy.