拷贝数扩增基因ENSA通过与HSP90结合促进LAR型三阴性乳腺癌增殖与耐药的机制研究

三阴性乳腺癌（TNBC）生物学恶性程度高、预后差、缺少已知靶点，是临床治疗难点。TNBC可进一步分为腔面雄激素受体型（LAR）等4-6个亚型。LAR型理论上抗雄治疗敏感，但实际临床缓解率低，疗效不佳。我们前期通过400余例TNBC标本的高通量测序，揭示了拷贝数扩增基因ENSA与LAR型TNBC的预后关系密切。结合前期预实验，我们提出科研假设：ENSA与HSP90结合后，通过经典配体依赖的AR-CCND1/CDK4与非配体依赖的PI3K/AKT-AR途径，促进LAR型的增殖与耐药。本项目将明确ENSA与HSP90互作的蛋白位点和效应机制、探索ENSA下游通路的具体模式、提出逆转耐药的临床策略。成果将为预测LAR型TNBC的临床结局并解决当前抗雄治疗敏感性不足的问题，提供创新思路。申请人具有良好研究基础，曾获国家自然科学基金资助，围绕着TNBC开展了系列研究。本项目是立足前期基础的深入拓展。

Triple-negative breast cancer (TNBC) is associated with highly aggressive biological feature, poor prognosis, and lack of known treatment targets. TNBC can be further classified into 4-6 subtypes such as luminal androgen receptor (LAR) subtype. The LAR subtype is theoretically sensitive to anti-androgen therapy, but the actual clinical response rate is low and the treatment outcome is not good. Our previous high-throughput sequencing of more than 400 TNBC specimens revealed that the amplification of ENSA gene is closely related to the prognosis of LAR subtype of TNBC. According to our previous preliminary experiments, we hypothesized that, ENSA might promote cell proliferation and drug resistance of LAR subtype by binding to HSP90 via classical ligand-dependent AR-CCND1/CDK4 and non-ligand-dependent PI3K/AKT-AR pathways. Our project aims to clarify the protein site and effect mechanism of the interaction between ENSA and HSP90, to explore the specific mode of the downstream pathway of ENSA, and to improve the strategy of clinical treatment. The results might provide the innovative ideas of predicting the clinical outcome of LAR subtype of TNBC and addressing the current problem of insufficient sensitivity to anti-androgen therapy. The applicant has adequate research experience and has been funded by National Natural Science Foundation of China. A series of researches have been carried out around TNBC by the applicant and this project is a systematic extension of the earlier studies.