长非编码RNA在乳腺癌Cyclin D1相关内分泌治疗耐药中的机制研究

About 50-70% of breast cancer are estrogen receptor positive and most of them are sensitive to endocrine therapy that against estrogen or estrogen receptor. However,one third of these patients will develop resistance to endocrine therapy and eventually relapse. Many studies indicate that the level of Cyclin D1 expression is closely related to the endocrine resistance of breast cancer. Recently, a large number of studies have shown that lncRNA play an important role in the regulation of tumor development. Further, LncRNA is shown to regulate the expression of cyclin D1. However, the role of lncRNA in endocrine resistance of breast cancer has not been reported. Our group will screen different expression of lncRNA in endocrine-resistant and Cyclin D1-overexpressed breast cancer cell lines.Then we will explore the role of lncRNA in regulating endocrine resistance of breast cancer cells by modulating the expression of selected LncRNAs. In addition, we will also analyze the mechanisms of lncRNA by studying their interation with signaling proteins and how the functional interactions regulate endocrine resistance. This study will look into the molecular mechanisms of endocrine resistance of breast cancer cells from a new approach and identify the LncRNAs associated with endocrine resistance. Moreover, it will provide new targets for the development of therapy against endocrine resistance.

雌激素受体阳性的乳腺癌占到了全部乳腺癌的50-70%，虽然这类乳腺癌大多对拮抗雌激素或其受体的内分泌治疗敏感，但大约三分之一的病人会产生耐药并复发。许多研究表明Cyclin D1表达水平与乳腺癌对于内分泌治疗的耐药密切相关。近期有大量的研究证明LncRNA在调控肿瘤发生发展中起重要作用，而且LncRNA可调控Cyclin D1的基因表达，但LncRNA与乳腺癌的内分泌耐药的关系尚未见报道。本课题组将筛选乳腺癌细胞内分泌耐药株或Cyclin D1过度表达株中差异表达的LncRNA，进一步在乳腺癌内分泌耐药模型中通过干预LncRNA表达，探索其对乳腺癌细胞对内分泌治疗反应的调控作用。此外，我们还将分析LncRNA与信号蛋白的结合作用机制，以及其如何参与调控乳腺癌细胞的内分泌耐药。本研究将为研究乳腺癌发生耐药的机制提供新的切入点，找到其相关的LncRNA，并为针对乳腺癌的耐药治疗提供新的治疗靶点

乳腺癌是女性好发肿瘤之一，其中，雌激素受体阳性的乳腺癌占到了全部乳腺癌的50-70%。虽然这类乳腺癌大多对拮抗雌激素或其受体的内分泌治疗敏感，但大约三分之一的病人会产生耐药并复发。为了深入了解乳腺癌内分泌耐药的机制，本课题成功建立了乳腺癌内分泌耐药株。进一步的实验结果表明，乳腺癌内分泌耐药株高表达E2F7可通过抑制miR-15a/16促进Cyclin E1 和 Bcl-2表达，继而调促进肿瘤细胞生长并引起耐药;LncRNAX/Cyclin D1 相关信号通道可逆转肿瘤内分泌耐药;乳腺癌内分泌耐药株中乳腺肿瘤祖细胞比例上调，并通过NFIA/IGF通路调控了内分泌耐药；乳腺癌内分泌耐药株通过高表达BRCA1/BARD1产生化疗抵抗，但可通过DNA损伤修复通路蛋白抑制剂逆转。近年来越来越多的文献报道，肿瘤微环境在调控肿瘤生长、转移和耐药中发挥着至关重要的作用。本课题组发现，长非编码RNA NKILA通过负性调控NF-kB通路抑制乳腺癌转移；间充质型乳腺癌细胞可促进肿瘤相关巨噬细胞分泌GM-CSF和CCL18，而GM-CSF 和CCL18反过来可以促进乳腺癌细胞EMT，成为一个正反馈循环等。本研究将为研究乳腺癌发生耐药的机制提供新的切入点，找到其相关的LncRNA和通路蛋白，为针对乳腺癌的耐药治疗提供新的治疗靶点。