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

14-3-3 在乳腺肿瘤进展中的代谢失调

• 批准号: 7962744
• 负责人: Dihua Yu
• 金额: $ 17.57万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7962744
• 关键词: 14-3-3 Proteins; Acinus organ component; Apoptosis; Biological; Brain; Breast Cancer Cell; Breast Diseases; Cancer cell line; Cell physiology; Cells; Cessation of life; Complex; Disease; Doctor of Medicine; Doctor of Philosophy; Down-Regulation; Doxycycline; Energy Supply; Epithelial Cells; Family; Gene Expression; Gene Mutation; Glucose; Glycolysis; Growth; Human; Hypoxia Inducible Factor; Knock-out; Knockout Mice; Link; Liver; Longitudinal Studies; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mus; Neoplasm Metastasis; Oxygen Consumption; Patients; Play; Predisposition; Process; Production; Proteins; Reaction; Recurrence; Role; Sampling; Small Interfering RNA; Staging; Structure; System; TP53 gene; Testing; Tetanus Helper Peptide; Tetracyclines; The Sun; Trans-Activators; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; aerobic glycolysis; base; cancer cell; cancer prevention; effective intervention; glucose uptake; in vivo; insight; malignant breast neoplasm; malignant phenotype; mammary epithelium; mammary gland development; mouse model; neoplastic cell; novel; overexpression; therapeutic target; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; uptake

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.

代谢放松管制是癌症进展过程中最初的肿瘤特异性改变之一，IS 被公认为癌症的第七个标志。有氧糖酵解增加为癌细胞提供了各种 太阳/ival和增长优势。 14-3-3蛋白参与许多重要的细胞过程。我们 发现在> 40％的乳腺癌中，14-3-3^过表达。 14-3-3^过表达显着 与患者的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^的过表达导致转化增加，凋亡减少，而 通过siRNA阻断14-3-3^的表达增加了凋亡并抑制肿瘤生长。令人兴奋的是，我们 最近发现MCFIOA乳腺上皮细胞（MEC）和乳房中的14-3-3^过表达 癌细胞导致糖酵解增加，而抑制14-3-3^表达降低了糖酵解。 此外，14-3-3^常规敲除小鼠的摄取减少了2-nbdg（荧光导数的 D-葡萄糖）在他们的肝脏和大脑中。 HI F1 A的激活称为主要机制之一 潜在的代谢重编程和14-3-3^的过表达也导致HLF1A的上调。基于 在这些上，我们假设1）1）14-3-3^调节乳腺肿瘤进展/转移和2）14-3-- 3T，介导的代谢失调可能在乳腺肿瘤进展中起关键作用。测试 假设，我们将建立可诱导的，乳腺特异性的14-3-3^转基因和敲除小鼠 使我们可以在体内定义明确的体内探索的模型14-3-3的复杂作用？在乳房中 肿瘤发生/转移和代谢失调（目标1和2）。我们将建立MEC和乳房 14-3-3的肿瘤细胞菌株？转基因和敲除小鼠，并使用它们来研究14-3-3？ 介导的代谢不导管在转化和肿瘤进展中起作用，确定 Hifia上调的机理14-3-3？及其对代谢放松管制的贡献和 转型（AIM3）。这些全面的方法将决定14-3-3的功能？在 乳腺发育，转化，肿瘤进展/转移以及14-3-的贡献 在这些过程中3？介导的代谢失调。