耐药是导致乳腺癌化疗失败的主要原因，目前却缺少有效的干预手段。MDM2，MDMX与p53 构成负反馈调节环参与肿瘤发生、凋亡、侵袭和转移，不少研究者认为MDM2/MDMX/p53通路同样参与化疗耐药的产生。课题组在前期研究中合成了靶向阻断MDM2/MDMX/p53通路的多肽-靶向 MDM2/MDMX小分子抑制剂，该多肽可抑制乳腺癌耐药细胞增殖，诱导TAB1蛋白表达水平增加。 因此我们提出假设:靶向MDM2/MDMX小分子抑制剂对乳腺癌化疗耐药具有逆转作用，同时TAB1可能参与介导MDM2/MDMX/p53通路逆转乳腺癌耐药的分子机制。本课题拟采用多种分子生物学方法明确该抑制剂是否能够逆转乳腺癌耐药，探讨TAB1在MDM2/MDMX/p53通路调控逆转乳腺癌耐药的具体分子机制。旨在为逆转乳腺癌耐药提供可能的靶向治疗药物,为阐明MDM2/MDMX/p53通路逆转耐药的具体机制提供理论基础和思路

Drug resistance is the main reason for clinical chemotherapy failure. However, the effective intervention is scarce. The negative feedback loop of MDM2/MDMX -p53 is proved to play a key role in determining tumor cell growth, apoptosis, invasion and metastasis, which is an important mechanism for the development of resistance to chemotherapy. Our previous study synthetized a polypeptide targeting the MDM2/MDMX/p53 circuitry, named MDM2/MDMX inhibitory protein, and showed that it inhibited drug resistance breast cancer cell proliferation, along with high expression of TAB1. Therefore，we hypothesized that the MDM2/MDMX inhibitory protein could reverse drug resistance in breast cancer, and MDM2/MDMX/p53 signal pathway regulated breast cancer cell drug resistance by the regulation of TAB1. This study will elucidate whether the inhibitory protein can reverse breast cancer cell drug resistance, and the mechanism of action of TAB1 in regulating MDM2/MDMX/p53 pathway. To provide a potential target drug for reversing breast cancer drug resistance, develop new ideas and offer theoretical basis for exploring the mechanism of MDM2/MDMX/p53 circuitry in breast cancer drug resistance.