他莫昔芬和芳香化酶抑制剂（Aromatase Inhibitors，AIs）是雌激素受体（ER）阳性乳腺癌病人临床常用药物。作为绝经后 ER 阳性乳腺癌患者的一线治疗方案，AIs 在疗效和耐受性方面优于他莫昔芬。然而，AIs 抵抗亦是治疗中的一个障碍。已有研究表明生长因子信号通路异常激活和ER表达和功能改变是 AIs 耐药的重要机制。但关于长链非编码 RNA（lncRNA）在 AIs 耐药中的角色鲜有报道。本研究旨在鉴定与 ER 结合、通过改变 ER 在基因组上的结合位点进而激活耐药相关基因表达的 lncRNAs，阐明 lncRNAs 对 ER 的调节机制，鉴定 lncRNAs-ER 调控的功能性靶基因，分析 lncRNAs 和候选基因与乳腺癌 AIs 治疗反应性的关系。此研究对于阐明 AIs 耐药的分子机制具有重要意义，为寻找有效的生物分子标志物及治疗靶点奠定重要基础。

Inhibition of estrogenic signaling by using anti-estrogens (e.g. tamoxifen), or using aromatase inhibitors (AIs), has been the main form of hormonal therapy for patients with estrogen receptor (ER)-positive breast cancer. Multiple clinical trials have been shown that AIs are more effective and better tolerated than tamoxifen as the first-line therapy for postmenopausal, ER-positive breast cancer. Unfortunately, resistance to AIs ultimately occurs. Potential mechanisms of resistance to AIs have been identified, often involving enhanced growth factor signaling and changes in the expression or action of the estrogen receptor, but few studies have addressed the role of long noncoding RNA (lncRNA). The goal of this study is to identify and characterize lncRNAs which function by binding with ER, and guide it throughout the genome to activate genes necessary for AIs resistance. We will determine how lncRNAs guide ER throughout the genome to activate specific gene targets necessary to promote resistance. We will also define key lncRNA-ER target genes which promote treatment resistance. We will finally assess the correlation between the expression of key lncRNAs and lncRNA-ER regulated target genes with response to AIs therapy in breast cancer patients. Successful completion of this project will significantly advance our understanding of the molecular mechanisms of AIs resistance. This research will also lay a foundation for putative biomarkers and new therapeutic strategies for breast cancer.