Role of Rab25 and its Effectors in Breast Cancer Bioengenerics

Rab25 及其效应子在乳腺癌生物工程中的作用

基本信息

批准号：
7962741
负责人：
GORDON B. MILLS
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/7962741
关键词：
1q22 8p11 AKT1 gene AKT2 gene Animal Model Anoikis Apoptosis Autophagocytosis Binding Bioenergetics Biological Markers Breast Breast Cancer Cell Bypass Cancer Prognosis Cancer cell line Cell Polarity Cell Proliferation Cell Surface Receptors Cell physiology Cell surface Cells Cellular Stress Competence Complex Coupling DNA DNA copy number Data Data Set Development Drug Delivery Systems EGF gene ERBB2 gene Endocytic Vesicle Endocytosis Endosomes Epidermal Growth Factor Receptor Equilibrium Family Frequencies Funding GTP Binding Gene Expression Profile Genes Genomics Glucose Glycogen Glycogen (Starch) Synthase Growth Guanosine Triphosphate Phosphohydrolases Hormone Receptor Hypoxia IGF1 gene Instruction Integrin Binding Integrins Lactation Lead Letters Ligands Link MAP Kinase Gene Maintenance Malignant Neoplasms Mammary gland Mediating Membrane Messenger RNA Methods Modeling Mus Mutate Mutation Neoplasm Metastasis Normal Cell Nuclear Receptor Coactivator 3 Nucleotides Nutrient Oncogenic Outcome Pathway interactions Patients Phase Phenotype Play Polyoma Virus Middle T Staining Method Protein Array Proteins Proteomics Proto-Oncogene Proteins c-akt RNA Recycling Regulation Role SLC2A1 gene Sampling Series Signal Transduction Signaling Molecule Stem cells Stress Testing Transgenic Model Vesicle Xenograft Model Xenograft procedure cell growth cell motility clinically relevant glucose uptake glycogen synthase kinase 3 beta improved in vivo interest malignant breast neoplasm member mutant novel outcome forecast overexpression programs rab GTP-Binding Proteins receptor reconstitution response scaffold trafficking tumor tumor growth tumorigenesis

项目摘要

During the current funding period, we demonstrated that Rab25 is a driver of the 1q22 amplicon in breast cancer contributing to tumor aggressiveness and a worsened outcome. Further Rab25: 1) DNA, RNA and protein levels are coordinately elevated in breast cancers, 2) DNA, RNA and protein levels as well as a Rab25 transcriptome correlate with patient outcomes, particularly in hormone receptor (HR) positive tumors, 3) levels are high in HR positive and HER2 positive tumors and low in basal/triple negative tumors, 4) is upregulated during cellular stress, 5) increases cell growth, colony formation, motility and invasion of breast cancer cells particularly under stress conditions, 6) inhibits stress-induced apoptosis and autophagy, and 7) increases growth of xenografts. Our operating hypothesis is that increased levels of Rab25 contribute to aggressiveness of breast cancer a n d worsened patient outcome by enabling breast cancer cells to survive hypoxia, nutrient and anoikis stresses present during cancer development and metastases through coordinate regulation of the P13K/AKT, LKB1/AMPK, and p27 pathways that mediate the decision to enter autophagy and/or apoptosis under nutrient stress conditions. We will test the hypothesis through the following aims: AIM 1. Determine the underlying mechanisms by which Rab25 contributes to breast cancer aggressiveness We will test the hypothesis that Rab25: 1) alters receptor and nutrient transporter internalization and recycling to the membrane, 2) improves bioenergetics, 3) alters the interplay between AKT and AMPK mediated regulation of p27, 4) alters expression or function of critical components of the apoptosis and autophagy cascades and 5) is sufficient to increase metastasis in breast cancer xenografts. AIM 2. Determine the role of Rab25 in initiation and progression of breast cancer using animal models. We will determine whether regulatable mammary specific expression of Rab25 is sufficient to alter breast development, regression and apoptosis post lactation or tumor development. Given the demonstration by Dr. Muller in this PPG that AKT plays a critical role in polyoma virus middle T (PyVmT) and erbB2 transgenic models and our preliminary data that Rab25 activates the P13K/AKT pathway, we will determine whether Rab25 alters the frequency or latency of breast cancer and metastases in tumor-prone mice expressing wild type PyVmT or activated erbB2 as well as PyVmT unable to link to the PISK pathway. AIM 3. Determine the role of Rab25 in breast cancer prognosis and outcomes Our preliminary data indicate that Rab25 DNA, RNA and protein levels as well as a Rab25 transcriptome correlate with patient outcomes, particularly in HR positive tumors. We will assess an independent large series of high quality breast cancer samples to determine whether a coordinate analysis of Rab25 DNA, RNA and protein levels or the Rab25 transcriptome will provide a robust method to predict patient outcomes and response to therapy.

在当前的资金期间，我们证明了Rab25是乳房中1Q22 Amplicon的驱动力癌症导致肿瘤侵袭性和结果恶化。 RAB25：1）DNA，RNA和蛋白质水平在乳腺癌中协同升高，2）DNA，RNA和蛋白质水平以及 RAB25转录组与患者结局相关，特别是在激素受体（HR）阳性肿瘤中， 3）HR阳性和HER2阳性肿瘤的水平高，基底/三重阴性肿瘤的水平很低，4）在细胞应激期间上调，5）增加细胞生长，落形成，运动和乳房的侵袭癌细胞尤其是在应力条件下，6）抑制压力诱导的凋亡和自噬，而7）异种移植物的生长增加。我们的操作假设是，RAB25的水平增加了通过使乳腺癌细胞能够使乳腺癌的侵略性和在癌症发育和转移过程中存在的缺氧，营养和厌氧菌应力通过p13k/akt，lkb1/ampk和p27途径的坐标调节决定在营养应激条件下进入自噬和/或凋亡。我们将测试通过以下目的假设： AIM 1。确定RAB25对乳腺癌贡献的潜在机制侵略性我们将测试Rab25：1）改变受体和营养转运蛋白的假设内部化和回收到膜，2）改善生物能学，3）改变之间的相互作用 AKT和AMPK介导的P27的调节，4）改变了临界成分的表达或功能凋亡和自噬级联反应和5）足以增加乳腺癌异种移植物的转移。 AIM 2。确定RAB25在使用动物的乳腺癌开始和进展中的作用型号。我们将确定Rab25的可调节性乳腺特异性表达是否足以改变哺乳或肿瘤发育后的乳房发育，消退和凋亡。给定演示穆勒博士在此PPG中，Akt在多头病毒中部T（PYVMT）和ERBB2中起着至关重要的作用 RAB25激活P13K/AKT途径的转基因模型和我们的初步数据，我们将确定 RAB25是否改变乳腺癌的频率或潜伏期和易于肿瘤的小鼠的转移表达野生型PYVMT或激活的ERBB2以及PYVMT无法链接到Pisk途径。 AIM 3。确定RAB25在乳腺癌预后的作用和我们的初步数据表明RAB25 DNA，RNA和蛋白质水平以及RAB25转录组与患者相关结果，特别是在人力资源阳性肿瘤中。我们将评估一系列独立的高质量乳腺癌样品确定RAB25 DNA，RNA和蛋白质水平的坐标分析还是 RAB25转录组将提供一种强大的方法来预测患者的结局和对治疗的反应。