YM155在逆转三阴性乳腺癌多药耐药中的作用及分子机制

At present, chemotherapy is the most essential means of breast cancer therapy, greatly improving the prognosis of breast cancer. In recent years, however, the appearance of chemotherapy resistance accounts for the limitation of chemotherapy choice,which seriously affected the therapy and prognosis of patients with breast cancer. Therefore,it has become a hotspot in the field of breast cancer therapy that finding new ways to overcome the chemotherapy resistance and investigating its underlined molecular mechanism, which is significant for breast cancer treatments and prognosis. Survivin, one of the members of apoptosis inhibiting protein gene family,is associated with chemotherapy resistance, but the mechanism is not clear so far. Our previous work showed that the expression of survivin increased significantly in the breast cancer cells resistant to paclitaxel or cisplatin. YM155，a kind of survivin inhibitors, will be used to investigate its ability of overcoming the resistance exhibited by the chemotherapy-resistant breast cancer cells in both apoptosis and movement aspects and the underling molecular mechanism. Our project provide theoretical basis for the combination of survivin inhibitors and therapeutic agents. And the mechanisms revealed in our research will provide a novel method on chemotherapy of breast cancer, which is essential for the treatment and prognosis of breast cancer.

三阴性乳腺癌（TNBC）在内分泌及靶向治疗效果不佳的情况下，以细胞毒药物为主的全身治疗成为其治疗首选。由于化疗耐药的出现，TNBC后续药物的选择受到限制，严重影响患者预后。Survivin是凋亡抑制蛋白家族成员，据报道，survivin与化疗耐药相关。YM155是一种新型survivin抑制剂，对乳腺癌细胞具有较高的敏感性。前期研究表明，在阿霉素耐药的乳腺癌细胞中，survivin表达显著增高。此外，YM155可显著降低耐药乳腺癌细胞中survivin表达，并通过促进凋亡、抑制增殖等方式影响乳腺癌细胞生存。我们还发现，Sp1可能介导YM155诱导的survivin转录下调。本课题将从细胞水平、动物模型两个方面系统研究YM155对TNBC多药耐药的逆转作用，并对其分子机制进行深入探讨。本研究为逆转TNBC多药耐药的临床治疗提供理论基础，为耐药乳腺癌的临床治疗提供新的潜在靶点。

乳腺癌是全球女性中最常见的癌症，化疗是乳腺癌治疗最重要的手段，其大大改善了乳腺癌患者的预后。Transforming growth factor-β （TGF-β）信号通路在乳腺癌上皮间质转化（epithelial to mesenchymal transition，EMT）和化疗药物耐药中发挥着相当重要的作用。本研究证实YM155可逆转三阴性乳腺癌多药耐药。分子机制上，YM155可上调一系列与TGF-β信号通路相关的miRNAs表达。SMAD2作为一个TGF-β信号通路的激活因子，可通过诱导EMT促进乳腺癌转移，诱导其耐药。本研究通过体外和体内实验证实miR-190可抑制乳腺癌转移。miR-190表达下调是TGF-β诱导EMT表型所必需的。同时，miR-190被ZEB1转录调控。我们还发现miR-190在乳腺癌组织表达下调，且与SMAD2表达呈负相关。另外，外源过表达miR-129抑制EMT，沉默miR-129表达诱导EMT。进一步研究发现Twist1是miR-129下游潜在的靶基因。同时Twist1和Snail能转录抑制miR-129表达。临床标本检测发现，miR-129-5p在乳腺癌组织中表达下调。miR-129低表达与乳腺癌患者较差的预后相关，且miR-129-5p与Twist1或Snail表达呈负相关。因此，本研究证实miR-129下调通过调控Twist1-Snail反馈环促进乳腺腺癌细胞EMT。本研究丰富了 TGF-β在乳腺癌进展的中所发挥的作用。