乳腺癌在女性癌症患者位居第一，死亡率居第二。死亡的主要原因是晚期转移。癌细胞在发生上皮细胞至间充质细胞转化（EMT）、获得干细胞CSC特性后，发生侵润、转移，在远位第二次生长, TGFbeta被证明在此过程中起关键作用。近年的研究显示肿瘤抑制因子LKB/AMPK与肿瘤的发生、发展和转移有关，但是，LKB1/AMPK和TGFbeta之间的关系从未有过研究报道。我们的初步研究结果表明，在乳腺癌细胞中，AMPK的激活可以抑制TGFbeta信号转导导通路，而抑制其下游蛋白LITAF的表达导致后者的激活，并上调EMT／CSC成分。因此，在本课题中，我们将进一步证实AMPK对EMT/CSC和TGFbeta信号通道的抑制作用，检测细胞学效应。并用乳腺原位异体移植肿瘤和转基因鼠动物模型确认AMPK对肿瘤转移抑制作用。本课题对于肿瘤转移的机制研究可以提供重要的信息，并为其防治提供新的依据和靶点。

Breast cancer is the most common cancer in women and the second cause for cancer deaths, for which the major cause is metastasis at a late stages. Some cancer cells undergo epithelial cell to messenchymal transition (EMT) and acquire features of cancer stem cells (CSC), such that they are able to invade, metastasize, grow and repopulate at distant sites. During this course, it has been well documented that TGFbeta plays a pivotal role. Recent studies have shown that the tumor suppressor LKB1 and its downstream effector, AMPK, are implicated in tumor onset, progression and metastasis; loss of function mutation of LKB1 is frequently found in human cancer and the mutation promotes tumor progression and metastasis; in breast cancer samples, it has been reported that AMPK activity is inhibited, the extent of which correlates to disease progression, whereas the TGFbeta signal pathway is upregulated. However, the relationship between AMPK and TGFbeta in cancer has never been reported. Our preliminary study in breast cancer cells has revealed that the activation of AMPK induces an inhibition of TGFbea signaling, whereas it is enhanced by suppression of AMPK and its downstream target LITAF, concurrent with changes in markers of EMT/CSC. Therefore, we hypothesize that during progression of breast cancer, AMPK is suppressed, which induces upregation of TGFbeta signaling, leading to EMT/CSC, a prerequisite condition for breast cancer metastasis. To test this hypothesis, we will expand our study by establishing more breast cancer cell lines expressing AMPK shRNA and overexpressing LKB1 and examining the effects of AMPK on EMT/CSC and TGFbeta signaling in association with malignant behaviors in vitro. We will also establish animal tumor models including othotopic Xenograft and transgenic mouse expressing the dominant negative AMPK mutant to demonstrate if inhibition of AMPK will lead to activation of TGFbeta and breast cancer metastasis. Altogether, our study will provide a novel view on the mechanism underlying AMPK regulation of tumorigenesis and progression. Therefore, completion of this study will provide us important insights into the mechanism of tumor metastasis and rationale for developing new drugs targeting AMPK for cancer therapy.