乳腺肿瘤中PI3K信号通路通常存在异常活化，驱动了肿瘤的快速增殖与药物耐受。二代测序技术的广泛应用揭示乳腺癌中广泛存在着PI3K基因（PIK3CA和PIK3R1）的突变，可能是该通路在乳腺肿瘤中异常激活的重要因素。然而，目前的研究尚缺乏针对PI3K突变的系统性功能注释，未能对大部分罕见、低频突变实现精准解读与对应治疗。基于此迫切需求，本项目拟采用多种先进的实验技术，系统性地解析乳腺癌中PI3K基因的驱动性（增殖、耐药）突变，包括：1）揭示中国乳腺癌人群中PI3K通路的突变谱系；2）采用自主研发的突变编码文库技术平台，筛选和鉴定乳腺癌PI3K驱动性（增殖、耐药）突变；3）探索利用PI3K通路抑制剂逆转PI3K 驱动性突变的策略及其内在机制。本项目的实施将有助于推动乳腺癌基因组数据的精准解读与对应治疗策略的探索，具有较高的转化性应用价值。

Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of breast tumour. The next generation sequencing advanced the knowledges that somatic mutations in PIK3CA and PIK3R1 are prevalent breast tumours which might determine the activation of PI3K pathway. However, there has not yet been a systematic study of somatic alterations in the PI3K pathway in breast cancer. Furthermore, our understanding of the functions of rare or novel mutations in this pathway has not kept pace with the discovery of individual mutations. In this project, we will like to perform works, as follow: 1) Investigation of somatic mutation profiles in Chinese breast cancer patients; 2) Identification of driver mutations which determine proliferation and drug resistance in PIK3CA and PIK3R1 via developing a recombination-based mutation barcoding (ReMB) library; 3) Exploration of PI3K pathway inhibitors for overcoming driver mutations and their underlying mechanisms. Collectively, these works will advance our understanding of genetic alterations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology.