Metabolic Deregulation by 14-3-3 in Mammary Tumor Progression

代谢失调是癌症进展过程中最早的肿瘤特异性改变之一， 被认为是癌症的第七个标志。有氧糖酵解增加为癌细胞提供各种 太阳/冰川和生长优势。14-3-3蛋白参与了许多重要的细胞过程。我们 发现14-3-3^在40%的乳腺癌中过度表达。14-3-3^的过度表达显著 与患者疾病复发和转移性死亡增加有关。在人类乳腺癌中 细胞，外源14-3-3^过表达导致转化增加，细胞凋亡减少，而 用siRNA阻断14-3-3的表达可促进细胞凋亡，抑制肿瘤生长。令人兴奋的是，我们 最近发现14-3-3^在MCFIOA乳腺上皮细胞(MECs)和乳房中过表达 癌细胞导致糖酵解增加，而抑制14-3-3^表达则减少糖酵解。 此外，14-3-3^常规基因敲除小鼠对2-NBDG(一种荧光衍生物)的摄取减少 肝脏和大脑中的葡萄糖)。HIF1α的激活是已知的主要机制之一 潜在的代谢重编程和14-3-3^的过度表达也导致了HlF1a的上调。基座 在此基础上，我们假设1)14-3-3调节乳腺肿瘤的进展/转移，2)14-3- 3T，介导的代谢紊乱可能在乳腺肿瘤的发生发展中起重要作用。要测试 假设，我们将建立可诱导的、乳腺特异的14-3-3^转基因和敲除小鼠 模型允许我们在定义明确的活体系统中探索14-3-3的复杂角色？在乳房 肿瘤发生/转移和代谢失调(目标1和2)。我们将建立微血管内皮细胞和乳腺 肿瘤细胞株来自14-3-3？转基因和基因敲除小鼠，并用它们来研究14-3-3？ 介导的代谢失控在转化和肿瘤进展中发挥作用，决定了 14-3-3上调HIFIA的机制？以及它对代谢放松管制的贡献和 转型(Aim3)。这些综合途径将决定14-3-3的功能。在……里面 乳腺发育、转化、肿瘤进展/转移及14-3-甲氧基异丁基异构酶的作用 3？-在这些过程中介导的代谢去调节。

Metabolic deregulation is one ofthe frst tumor-specific alterations during cancer progression and is recognized as the seventh hallmark of cancer. Increased aerobic glycolysis provides cancer cells various sun/ival and growth advantages. The 14-3-3 proteins are involved in many important cellular processes. We discovered that 14-3-3^ is overexpressed in >40% of breast cancers. 14-3-3^ overexpression is significantly associated with increased disease recurrence and metastatic death of patients. In human breast cancer cells, overexpression of exogenous 14-3-3^ led to increased transformation, reduced apoptosis, whereas blocking 14-3-3^ expression by siRNA increased apoptosis and inhibited tumor growth. Excitingly, we recently found that 14-3-3^ overexpression in both MCFIOA mammary epithelial cells (MECs) and breast cancer cells led to increased glycolysis, whereas inhibiting 14-3-3^ expression decreased glycolysis. Moreover, 14-3-3^ conventional knockout mice had reduced uptake of 2-NBDG (a fluorescent derivative of D-glucose) in their livers and brains. Activation of HI F1 a is known as one ofthe principal mechanisms underlying metabolic reprogramming and 14-3-3^ overexpression also led to upregulation of HlF1a. Based on these, we hypothesize that 1) 14-3-3^ modulates mammary tumor progression/metastasis and 2) 14-3- 3t,-mediated metabolic deregulation may play a critical role in mammary tumor progression. To test the hypothesis, we will establish inducible, mammary gland-specific 14-3-3^ transgenic and knockout mouse models that allow us to explore in well-defined in vivo systems the complex roles of 14-3-3? in mammary tumorigenesis/metastasis and metabolic deregulation (Aims 1 & 2). We will establish MECs and mammary tumor cell strains from 14-3-3? transgenic and knockout mice and use them to investigate whether 14-3-3?- mediated metabolic deregulation plays a role in transformation and tumor progression, determine the mechanisms of HIFia upregulation by 14-3-3? and its contribution to metabolic deregulation and transformation (Aim3). These comprehensive approaches will determine the functions of 14-3-3? in mammary gland development, transformation, tumor progression/metastasis, and the contribution of 14-3- 3?-mediated metabolic deregulation in these processes.