TGF-β通过miR-21和miR-181调控乳腺癌化疗耐药机制的研究

化疗药物耐药是乳腺癌治疗失败的重要因素之一，TGF-β高表达的乳腺癌患者易出现化疗耐药。课题组在已有发现乳腺癌中TGF-β通过miR-21和miR-181分别下调MSH2和ATM表达的工作基础上，提出TGF-β依据p53功能状态的不同通过调控miR-21/MSH2和/或miR-181/ATM途径及其信号传导通路相关基因的表达进而使乳腺癌特别是基底细胞样乳腺癌对化疗药物导致的DNA损伤的耐受性增强而出现耐药的设想。课题组将通过检测不同p53功能状态乳腺癌细胞中TGF-β及以上信号传导通路相关因素的改变对各种类型化疗药物处理后的影响，包括耐药性改变、DNA双链断裂反应、不同细胞凋亡途径反应等各种指标对上述设想进行研究，最后进行临床标本的验证。其成果可望为深入了解乳腺癌中TGF-β介导的化疗耐药机制以及发现新的治疗靶点提供新途径。

Chemoresistance is an important factor in breast cancer relapse. High levels of TGF-β in breast cancers correlate with their chemoresistance. MSH2 and ATM are both known to involve in DNA damage response and we have recently reported that TGF-β downregulates MSH2 and ATM in p53 active breast cancer cells through inducing miR-181 and miR-21 respectively,while only downregulates MSH2 in p53 inactive cells. Based on these prelimitary work,we hypothesize that TGF-β induces resistance to genotoxic chemotherapy through disrupting DNA damage response in breast cancer cells especially in the basal-like breast cancer by regulating the MSH2/miR-21 and/or ATM/miR-181 signaling pathway and their associated genes depending on the p53 functionality. we will try to examine the effects of TGF-βand other factors involved in the above signaling pathway on the cell response(including chemosensitivity、DSB response、apoptotic pathways response) to different types of chemo-drugs in breast cancer cell lines with different p53 functionality and further confirm our hypothesis by clinical samples. Our study will provide new ways to define the mechanism of TGF-βmediated breast cancer chemoresistance and to identify novel therapeutic targets for breast cancer therapy.