三阴性乳腺癌（TNBC）预后差于腔面型（Luminal），放射抵抗是其不良预后原因之一。我们前期研究表明：GADD45α通过调控自噬与凋亡介导TNBC放射抵抗。沉默GADD45α基因或促进其泛素化降解可增加TNBC放射敏感性。据此我们提出假说：GADD45α处于肿瘤细胞命运十字路口，射线可抑制MDM2介导GADD45α泛素化降解，导致GADD45α积聚并通过JNKs/c-Jun及ULK1-PIK3C通路调控凋亡与自噬，维持肿瘤细胞内环境稳态介导放化疗抵抗。AMG232可抑制MDM2-p53相互作用促进GADD45α泛素化。为证明此假说，本项目将采用放射生物学研究方法探索射线导致GADD45α积聚并多向调控细胞凋亡与自噬从而介导TNBC放射抵抗的机制；同时本项目将验证MDM2抑制剂AMG232的放射增敏作用，深入研究GADD45α、自噬、凋亡与TNBC放射抵抗的调控关系，寻找放射增敏靶点。

The prognosis of triple negative breast cancer (TNBC) is worse than Luminal type, and radiation resistance is one of the reasons for its poor prognosis. Our previous research showed that GADD45α mediated TNBC radiation resistance by regulating autophagy and apoptosis. Silencing GADD45α gene or promoting its ubiquitination degradation can increase TNBC radiosensitivity. Therefore, we proposed a hypothesis: GADD45α is at the crossroads of the fate of tumor cells, and radiation can inhibit MDM2-mediated degradation of GADD45α ubiquitin, leading to GADD45α accumulation, which regulate apoptosis and autophagy through JNKs/c-Jun and ULK1-PIK3C pathways, maintain the homeostasis of tumor cells, and mediate its resistance to chemoradiotherapy. AMG232 can inhibit the interaction of MDM2-p53 and promote the degradation of GADD45α ubiquitination. To prove this hypothesis, this project will use radiobiological research methods to explore the mechanism of radiation inhibition of MDM2-mediated degradation of GADD45α ubiquitination, leading to GADD45α accumulation, and the accumulated GADD45α multipathway regulates apoptosis and autophagy, thereby mediating TNBC radiation resistance. At the same time, this project will verify the radiosensitization effect of the MDM2 inhibitor AMG232, further study the regulatory relationship between GADD45α, autophagy, apoptosis and TNBC radio-resistance, and search for potential radiosensitization targeted drugs.