乳腺癌骨转移是患者治疗失败和死亡的主要原因。骨转移前微环境的形成为转移干预带来新思路，但形成机制有待阐明。ULK1介导了缺氧条件下线粒体自噬的发生。我们发现ULK1在乳腺癌低表达，且低表达的患者易发生骨转移，ERK激酶可能介导了其泛素化蛋白酶体降解；在实验性骨转移模型上，ULK1敲低组的小鼠易形成转移前溶骨性病灶；炎症因子芯片显示ULK1缺失时多种因子分泌增加。本课题拟阐明ERK磷酸化ULK1导致其发生β-TRCP介导的泛素化降解的机制；构建线粒体自噬缺陷的肿瘤模型，探讨其通过破坏破骨细胞与成骨细胞间的平衡形成转移前溶骨性病灶，并明确该病灶促进癌细胞定植于骨；鉴定在其中起关键作用的特异性炎症因子，及其促使骨髓源性抑制细胞/巨噬细胞分化为破骨细胞的分子机制；明确阻断特异性炎症因子的抗体和ERK抑制剂单药或联用对骨转移的影响，从中筛选出最佳用药方案，为乳腺癌骨转移的防治提供新策略。

Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable. The formation of pre- metastatic bone niche provide a "nutrition centers" for subsequent breast cancer cell colonization. However, the molecular interactions governing the early events of osteolytic lesion formation are currently unclear. ULK1 is critical for the induction of mitophagy under hypoxia, In our preliminary study, we found that ULK1 protein levels decreased in breast cancer tissues, and the patients with low expression ULK1 are more susceptible to bone metastasis. ERK kinase may be involved in the ULK1 ubiquitin proteasome degradation. And in experimental bone metastasis animal models, ULK1-knockdown tumor-bearing mice had significantly increased numbers of pre-metastatic focal osteolytic lesions compared to WT tumor-bearing mice. Human inflammation antibody array showed increased secretion of specific cytokines in breast cancer cells with ULK1 knockdown. In this proposal, we will further explore mechanisms that phosphorylation of ULK1 by ERK kinase triggers its interaction with SCFβ-TRCP, and subsequent ubiquitination and destruction. We will establish the mitophagy-deficient models, and investigate the loss of mitophagy induces breast cancer pre-metastatic bone lesions by disrupting the balance between osteoclasts and osteoblasts，and confirm the pre-metastatic preparation of secondary sites facilitate subsequent breast cancer cells colonization. We will identify the key specific inflammatory cytokines secreted by mitophagy-deficient cells, and extend the molecular mechanisms that regulate myeloid-derived suppressor cells / macrophage cells differentiation into osteoclasts by these cytokines. We will propose potential therapeutic strategies by using antibodies targeting the key specific inflammatory cytokines alone and /or with inhibitors targeting ERK kinase, and validate their anti-tumor efficacy in mice bone metastasis models. Overall, this study will improve our understanding of mitophagy and provide new strategies for breast cancer bone metastasis treatment.