MnSOD Acetylation Promotes Cancer Stem Cell Phenotypes in Breast Cancer

项目摘要/摘要： 肿瘤干细胞是肿瘤中一种罕见但极其重要的细胞亚群。 与治疗失败和转移复发有关。尽管它正变得越来越多 显然，针对这一亚群的治疗可能会带来更好的治愈几率 未知这些细胞是如何起源的，以及促进这些细胞的生化过程是什么 癌症中的“茎”。我们实验室发现线粒体代谢的改变 活性氧促进缺氧诱导因子2α的异常激活 (HIF2α)。Hif2α的激活是一种成熟的茎形成机制，也 与乳腺癌患者的转移复发和治疗失败有关 癌症。我们发现一种主要酶的翻译后修饰(即乙酰化) 参与线粒体ROS代谢的锰超氧化物歧化酶(MnSOD) 破坏具有抗氧化功能的四聚体结构，将酶转化为单体 这促进了ROS的形成并激活了HIF2α。我们还发现MnSOD-K68Ac 在表达低雌激素受体水平的乳腺癌中显著积累。因此，它是 提出了MnSOD具有作为肿瘤抑制因子的二分性 启动(抗氧化功能)，但仍促进稍后的癌症干细胞重新编程 已确诊的肿瘤。这一命题得到了以下发现的支持： 转移灶与原发肿瘤组织中MnSODHIF2α信号的比较 来自相同的乳腺癌患者。因此，本申请旨在确定：(1)如果 MnSOD-Ac将肿瘤细胞重新编程为与化疗耐药相关的干细胞表型。 (2)如果在已建立的肿瘤中进行生化和/或基因靶向的MnSODAc或HIF2α 携带MnSODHigh/Hif2α信号的小鼠(MMTV.PyVT)抑制化疗耐药性和/或 转移。(3)如果乳腺癌患者的亚群之间存在关联， 表现出MnSODHigh或MnSODAc，或MnSODROS-HIF2α分子轴签名和 出现化疗耐药或增加转移复发的风险。

PROJECT SUMMARY / ABSTRACT: Cancer stem cells are a rare and yet critically important subpopulation of cells in tumors associated with treatment failure and metastatic recurrence. Though it is becoming increasingly clear that targeting this subpopulation could lead to therapies with better odds of a cure it is still unknown how these cells originate and what are the biochemical processes that promote “stemness” in cancer. Our laboratory found that alterations in the metabolism of mitochondrial reactive oxygen species (ROS) promote aberrant activation of hypoxia-induced factor 2α (HIF2α). The activation of HIF2α is a well-established mechanism of stemness that has also been implicated in metastatic recurrence as well as treatment failure in women with breast cancer. We found that a posttranslational modification (i.e. acetylation) of a primary enzyme involved in the metabolism of mitochondrial ROS, manganese superoxide dismutase (MnSOD) breaks the tetrameric structure that has antioxidant function turning the enzyme into a monomer that promotes ROS formation and activates HIF2α. We also found that MnSOD-K68Ac accumulates prominently in breast cancers expressing low estrogen receptor levels. Hence, it is proposed that MnSOD has a dichotomous behavior functioning as a suppressor of tumor initiation (antioxidant function) and yet promotes cancer stem cell reprogramming later on in established tumors. This proposition is supported by the finding of strong associations between a MnSOD/HIF2α signature present in metastatic lesions compared to primary tumor samples from the same breast cancer patients. Hence, this application aims at determining: (1) if MnSOD-Ac reprograms tumor cells to stem-like phenotypes associated with chemoresistance. (2) if the biochemical and/or genetic targeting of MnSOD-Ac or HIF2α in established tumors of mice with the MnSODhigh/HIF2α signature (MMTV.PyVT) suppresses chemoresistance and/or metastasis. (3) if there is an association between subsets of women with breast cancer that exhibit a MnSODhigh or MnSOD-Ac, or MnSOD-ROS-HIF2α molecular axis signature and develop chemoresistance or have increased risk of metastatic recurrence.