线粒体功能参与介导乳腺癌转移是近来的研究热点，然而线粒体与转移机制的联接点是一个缺失环节。我们的前期研究显示线粒体蛋白CHCHD2在乳腺癌中高表达并与不良预后相关。对于CHCHD2的分析发现该蛋白通过其富含半胱氨酸的CX9C结构域感应细胞外的氧应激，由还原态的单体转化为氧化态的寡聚体，导致蛋白构象变化并由线粒体释放进入细胞质和细胞核，这一系列的变化为线粒体蛋白CHCHD2调控非线粒体信号如转移机制提供了空间基础。本课题将致力于从分子、细胞、动物模型以及临床样本的不同层次研究CHCHD2与乳腺癌转移的关系，并将结合蛋白质组学以及基因表达差异显示芯片发现CHCHD2调控肿瘤转移的分子机制。本课题的成功实施将为理解线粒体如何参与并介导癌症尤其是乳腺癌转移提供新的思路，同时可以为晚期转移乳腺癌提供新的肿瘤标志物甚至是药物靶标。

Escalating evidences suggest that mitochondrion is indispensible for metastatic breast cancer. However, the linker between mitochondria and metastasis signaling is missing. Recently, we found that CHCHD2, a mitochondrial protein involved in the regulation of oxidative phosphorylation, is highly expressed in breast cancer patient samples. Moreover, high level of CHCHD2 is statistically correlated with worse prognosis in breast cancer patients. Biochemistry studies revealed that CHCHD2 is able to sense high ROS, which is one of the hallmarks in tumor microenvironment. By neutralizing ROS through its CX9C motif, CHCHD2 changes its conformation and translocates from mitochondria to cytoplasm and nuclear where it acquires the allosteric potential to crosstalk and trigger non-mitochondrial events such as metastasis. Meanwhile, loss of CHCHD2 from mitochondria could cause mitochondrial dysfunction and caner beneficial metabolic reprogramming. In this current proposal, we will study the relationship between CHCHD2 and metastatic mechanisms with in vitro and in vivo system. We will also recruit proteomics method as well as differential display microarray to further uncover the downstream signals which are related to the regulation of metastasis by CHCHD2. This study will provide insight in understanding how mitochondria machinery mediates cancer metastasis. The fulfillment of this proposal will also shed light on the discovery of novel therapeutic targets for metastatic breast cancer.