TPD52基因的拷贝数在乳腺癌中会扩增，其高表达与乳腺癌的不良预后有关。但TPD52的扩增是否有助于肿瘤发生尚不清楚。我们前期研究证实TPD52在多种乳腺癌细胞系及临床肿瘤样本中高表达，并且其表达可以被NFκB信号转导通路调控；进一步研究发现TPD52能负调控AMPK激酶的活性。LKB1-AMPK途径已被发现在抑制肿瘤细胞生长和能量代谢中起重要作用。迄今为止，TPD52是第一个与AMPK复合物直接相互作用的调控蛋白。基于以上研究结果，我们设定本研究目标为：1）用乳腺癌细胞作为研究模型来探索TPD52在AMPK通路中的调控功能及其分子机制；2）以临床样本及转基因小鼠模型分析探讨其在肿瘤发生和治疗中的作用。本课题的开展将为TPD52在乳腺癌中高表达和AMPK信号通路调控提供新的重要见解，弥补我们对于在多种肿瘤中扩增并过表达基因的认知不足，并针对TPD52高表达肿瘤的治疗提供思路。

Breast cancer is the most common cancer and the second leading cause of cancer death in women. Better understanding breast cancer etiology would help prevent and treat this disease. The tumor protein D52 (TPD52) gene maps to a region on chromosome 8q21 that is commonly amplified in many tumors, and it is also associated with poor prognosis in cancers such as breast cancer. It remains unclear whether TPD52 amplification passively reflects its gene location or actively contributes to tumorigenesis. In addition, TPD52 is commonly overexpressed in breast cancer,but how TPD52 is regulated at the transcriptional level remains unclear. In preliminary studies, we found that TPD52 expression can be regulated by NFkB pathway. We also found that TPD52, as previously reported, is overexpressed in multiple breast tumor cell lines as well as clinical tumor samples and that alteration of TPD52 expression levels changes cell proliferation rate. To further explore its function, we performed an in vitro pulldown assay followed by mass spectrometry, and we found that AMPK interacts with TPD52, which was confirmed by Co-Immunoprecipitation (Co-IP). We further demonstrated that TPD52 negatively regulates AMPK activity, possibly through a phosphorylation-dependent process. The LKB1-AMPK pathway has been identified as the central regulator of energy metabolism and growth control in tumor suppression. AMPK activators such as metformin, a drug used to treat type II diabetes, have shown beneficial effect in cancer prevention and treatment. In the current application, we propose the following Specific Aims : 1）To study how TPD52 levels are regulated and how TPD52 regulates AMPK activity and downstream pathways. 2）To study how the interaction between TPD52 and AMPK is regulated upon activation of AMPK. 3）To determine the role of TPD52 in breast cancer tumorigenesis using clinical samples and transgenic mouse models. These studies will reveal a novel role of TPD52 in the regulation of an extremely important pathway, the AMPK pathway, which is involved in energy metabolism,autophagy and cell proliferation.