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

基本信息

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
项目类别：
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

项目摘要

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.

代谢失调是癌症进展过程中第一个肿瘤特异性改变之一，被认为是癌症的第七个标志。有氧糖酵解的增加为癌细胞提供了多种阳光/伊瓦尔和生长优势。 14-3-3 蛋白参与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^ 过表达显着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中，外源 14-3-3^ 的过度表达导致转化增加，细胞凋亡减少，而通过 siRNA 阻断 14-3-3^ 表达可增加细胞凋亡并抑制肿瘤生长。令人兴奋的是，我们最近发现 14-3-3^ 在 MCFIOA 乳腺上皮细胞 (MEC) 和乳腺中过度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^ 传统基因敲除小鼠对 2-NBDG（2-NBDG 的荧光衍生物）的摄取减少 D-葡萄糖）存在于他们的肝脏和大脑中。 HI F1 a 的激活被认为是主要机制之一潜在的代谢重编程和 14-3-3^ 过度表达也导致 HlF1a 的上调。基于基于这些，我们假设 1) 14-3-3^ 调节乳腺肿瘤进展/转移，2) 14-3- 3t，介导的代谢失调可能在乳腺肿瘤进展中发挥关键作用。测试假设，我们将建立可诱导的乳腺特异性 14-3-3^ 转基因和敲除小鼠使我们能够在明确的体内系统中探索 14-3-3 的复杂作用的模型？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 和乳腺 14-3-3 的肿瘤细胞株？转基因和基因敲除小鼠并用它们来研究是否 14-3-3?- 介导的代谢失调在转化和肿瘤进展中发挥作用，决定 14-3-3 上调 HIFia 的机制？及其对代谢失调的贡献转型（目标 3）。这些综合方法将决定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 3? 介导这些过程中的代谢失调。