铜离子通过直接结合PDK1激活AKT通路促进乳腺癌的发生

乳腺癌是一种危害女性健康的重大疾病，而其早期转移是肿瘤病人死亡的主要原因。因此发现新的乳腺癌发生及转移相关的标记物及关键靶点是目前急需解决的临床问题。近期研究显示，肿瘤微环境中微量金属离子的改变，尤其是铜离子（Cu）的增高是促进乳腺癌增殖、转移的一个重要诱因。在我们的研究中发现，铜离子可以直接结合PDK1激酶，通过促进PDK1激酶与其底物AKT的结合，来增强AKT激酶的活性，从而促进乳腺癌肿瘤细胞的增殖、转移及对化疗药物的耐药性。同时，我们发现乳腺癌细胞中铜离子浓度的增高是由于其转运通道蛋白CTR1表达增高引起的。在此研究基础上，将进一步研究CTR1在乳腺癌发生、转移中的重要临床意义，CTR1在乳腺癌中过表达的机制，铜离子对PDK1/AKT通路的激活机理，及CTR1/Cu这一通路在乳腺癌耐药及转移中的重要作用，最终揭示铜离子螯合剂对乳腺癌发生和转移的治疗效果。

Breast cancer is one of the deadliest cancers in women due to its aggressiveness and poor survival rate. Given that early metastasis and drug resistance are the major cautions for the poor outcome of the breast cancer patients, discovering the novel biomarkers for breast cancer early diagnosis, investigating the key oncogenic pathways governing breast cancer metastasis and developing the target therapy for these key oncoproteins are the urgent aims for combating breast cancers. Meanwhile, tumor microenvironment provides a niche for tumor growth, drug resistance and metastasis, in which the trace elements including the metal ions have been revealed to play pivotal roles for tumorigenesis. To this end, we demonstrate that copper activates the PI3K/AKT oncogenic signaling pathway to facilitate tumorigenesis. Mechanistically, copper directly binds PDK1, in turn promoting PDK1 binding and subsequently activating its downstream substrate AKT to promote cell malignancies. Blocking the copper transporter 1 (CTR1)/copper axis by either depleting CTR1 or through the use of copper chelators diminishes AKT activity and reduces breast cancer tumorigenesis. In support of an oncogenic role for CTR1, we find that CTR1 is abnormally elevated in breast cancer, especially in the triple negative breast cancers (TNBC), which is subjected by a Nedd4l-mediated negative regulation through ubiqutination and subsequent degradation. Thus, our findings not only identify a novel regulatory crosstalk between the Nedd4l/CTR1/copper axis and the PDK1/AKT oncogenic signaling, but also highlight the therapeutic relevance of targeting the CTR1/copper node for the treatment of hyperactive AKT-driven cancers.