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

• 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
• 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

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.

在目前的资助期间，我们证明了Rab 25是乳腺癌中1 q22扩增子的驱动因子。 癌症导致肿瘤侵袭性和恶化的结果。进一步Rab 25：1）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 Rab 25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)水平在HR阳性和HER 2阳性肿瘤中高，而在基础/三阴性肿瘤中低，4） 在细胞应激期间上调，5）增加细胞生长、集落形成、运动性和乳腺侵袭 特别是在应激条件下的癌细胞，6）抑制应激诱导的细胞凋亡和自噬，和7） 增加异种移植物的生长。我们的操作假设是Rab 25水平的增加有助于 乳腺癌的侵袭性，并通过使乳腺癌细胞 在癌症发展和转移过程中存在的缺氧、营养和失巢凋亡应激中存活 通过协调调节P13 K/AKT、LKB 1/AMPK和p27通路，介导 决定在营养胁迫条件下进入自噬和/或凋亡。我们将测试 假设通过以下目的： AIM 1.确定Rab 25导致乳腺癌的潜在机制 我们将检验Rab 25：1）改变受体和营养转运蛋白的假设 内化和再循环到膜，2）改善生物能学，3）改变 AKT和AMPK介导的p27调节，4）改变了细胞内关键成分的表达或功能。 细胞凋亡和自噬级联和5）足以增加乳腺癌异种移植物中的转移。 AIM 2.使用动物实验确定Rab 25在乳腺癌发生和发展中的作用 模型我们将确定Rab 25的可调控乳腺特异性表达是否足以改变乳腺癌的发生。 乳腺发育、退化和哺乳后细胞凋亡或肿瘤发展。鉴于示威游行 Muller博士在本PPG中指出，AKT在多瘤病毒中间T（PyVmT）和erbB 2中起着关键作用。 转基因模型和我们的初步数据，Rab 25激活P13 K/AKT途径，我们将确定 Rab 25是否改变了肿瘤易感小鼠乳腺癌和转移的频率或潜伏期 表达野生型PyVmT或活化的erbB 2以及不能连接到PISK途径的PyVmT。 AIM 3.确定Rab 25在乳腺癌预后和结果中的作用 表明Rab 25 DNA、RNA和蛋白质水平以及Rab 25转录组与患者相关 结果，特别是在HR阳性肿瘤中。我们将评估一个独立的大系列的高质量 乳腺癌样本，以确定是否Rab 25 DNA，RNA和蛋白质水平的坐标分析，或 Rab 25转录组将提供预测患者结果和对治疗的反应的可靠方法。