LncRNAs通过调控ER转录程序介导芳香化酶抑制剂耐药的分子机制研究

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.

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。

乳腺癌（BCa）的发病率和死亡率位居女性恶性肿瘤的第一位，因此寻求一些更有效的治疗方案已成为当务之急。雌激素受体α（ERα）在大约70％的乳腺癌中呈阳性表达。雌激素与受体结合并激活雌激素受体（ER）信号，并在乳腺癌的发生和发展中起重要作用。在临床上，ERα表达与乳腺癌患者的预后相关，因此被认为是内分泌治疗的重要靶标。针对ERα的抑制剂，例如，他莫昔芬、氟维司群和芳香化酶抑制剂已被用于ERα阳性乳腺癌患者的抗雌激素治疗，显著改善了患者预后。然而，随着疾病的进展，许多接受内分泌治疗的患者产生了获得性耐药。因此，阐释乳腺癌内分泌耐药机制，对鉴定内分泌治疗新靶点、开发新的治疗策略具有重要的意义。为了深入阐释以转录因子ER为核心的基因表达调控异常介导芳香化酶抑制剂耐药的分子机制，我们建立了乳腺癌内分泌治疗敏感和耐药的体外细胞模型MCF-7和LETD细胞对，以此细胞对为研究材料，进行了RNA-Seq、ER ChIP-Seq、ATAC-Seq、WGBS、H3K27Ac 和H3K4me1 ChIP-Seq等多维组学分析，系统整合多维度多层次表观遗传调控组学数据发现LINC00865和XIST通过结合ER/AR调控ER/AR表达，FOXA1/ER转录调控轴是敏感细胞中重要的功能通路，而AP-1是耐药细胞中显著富集的转录因子。ER/AP-1靶基因S100A14通过调控CCL2/CXCL5通路促进乳腺癌细胞上皮间质转化、肿瘤干性和转移。未来研究中，拟继续从DNA甲基化、组蛋白修饰和转录因子结合交互调控的角度鉴定乳腺癌内分泌治疗耐药的增强子和超级增强子调控的关键靶基因，深入阐释其表观遗传调控机制，鉴定新型靶点和治疗策略。