TMSB10诱导三阴性乳腺癌放疗抵抗的分子机制

Adjuvant radiotherapy is very important for the treatment of breast cancer, and radioresistance is the main cause of recurrence and metastasis in triple negative breast cancer(TNBC). Previously, we identified that thymosin beta 10 (TMSB10) plays an important role in the development and progression of breast cancer (Breast Cancer Res. 2017.IF=6.345, corresponding author). Recently, we found that TMSB10 was significantly up-regulated in triple negative breast cancer cells which led to radioresistance. The potential mechanisms include: TMSB10 regulates TGF-β signaling pathways against apoptosis of breast cancer cells; TMSB10 activates ATM pathway to enhance cell DNA damage repair ;TMSB10 regulates PI3K/AKT pathway to enhance proliferation ability after radiation; TMSB10 are regulated by ALG3 to induce the breast cancer radioresistance. However, the molecular mechanisms that TMSB10 induced radioresistance in triple negative breast cancer are still unknown. Therefore, this project aims to integrate molecular biology, cell biology and animal experimental models, employ ionizing radiation, and analyze clinical specimen data, to further investigate the mechanisms that TMSB10 affects radioresistance in triple negative breast cancer, which may provide new biomarkers and targets for the diagnosis and treatment of radioresistance in triple negative breast cancer to increase the efficacy of radiotherapy.

放疗是三阴性乳腺癌的重要治疗手段，而放疗抵抗是导致肿瘤复发转移的主要原因。我们的前期研究 【Breast Cancer Res. 2017. IF=6.345，通讯作者】已证明β-胸腺肽10 (TMSB10) 对乳腺癌发展起重要作用；近期，我们又发现TMSB10在三阴性乳腺癌细胞中显著扩增并异常高表达，导致放疗抵抗，其可能的机制是：①调控TGF-β信号通路使肿瘤细胞抗凋亡；②激活ATM通路增强肿瘤细胞DNA损伤修复， ③调控PI3K/AKT信号通路促进乳腺癌细胞放疗后再增殖；④受ALG3糖基化调控，表达水平上调。然而，TMSB10诱导三阴性乳腺癌放疗抵抗的具体分子机制尚不明确。本研究拟综合分子、细胞生物学及动物模型实验，采用电离辐射等方法，结合临床标本，深入探讨TMSB10诱导放疗抵抗的分子机制，为三阴性乳腺癌放疗抵抗的诊治提供新的分子标志物及靶点，从而提高三阴性乳腺癌放疗疗效。

三阴型乳腺癌（TNBC）为乳腺癌中预后较差的类型，而放疗抵抗性是导致TNBC复发转移最重要原因之一。前期研究证明β-胸腺肽10(TMSB10) 在乳腺癌恶性发展中起重要作用。然而，TMSB10是否可以诱导TNBC发生放疗抵抗依旧缺乏相应的研究。我们在三阴性乳腺癌细胞中构建TMSB10高表达和低表达稳株，进行电离辐射，采用平板克隆、MTT实验、TUNEL、细胞凋亡检测等实验测定TMSB10 对放射线处理后TNBC细胞系存活的影响，并通过WB、免疫荧光等实验验证ATM、NF-κB和STAT3信号通路的影响，并从临床角度探索TMSB10与预后的关系。通过实验发现，TMSB10在TNBC细胞中显著扩增、异常高表达，并导致放疗耐受。其机制包括：TMSB10靶向激活ATM信号通路，促进DNA损伤修复，并通过激活NF-κB、STAT3信号通路使肿瘤细胞发生抗凋亡的特性，并增强TNBC干细胞自我更新能力及促进下游抗调亡基因的表达，从而促进细胞增殖。进一步发现ALG3可通过调控糖基化过程进而调控TMSB10。ALG3可增强乳腺癌干细胞样特征，在辐射抵抗的乳腺癌组织中显著高表达，与患者的不良预后相关，最终导致肿瘤细胞的放疗抵抗。本课题综合细胞及分子生物学，并结合临床标本分析，深入探讨TMSB10诱导TNBC放疗抵抗的分子机制，为早期预测TNBC放疗抵抗提供新的理论依据，为治疗提供新的靶点。