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Transcriptional regulation of tumor growth

肿瘤生长的转录调控

基本信息

批准号：
9275399
负责人：
ANTONINO PASSANITI
金额：
--
依托单位：
BALTIMORE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275399
关键词：
6p21 Address African American Age Aging Appearance Biological Assay Breast Cancer Cell Breast Epithelial Cells Cancer Death Rates Cancer Patient Cardiovascular Diseases Cell Differentiation process Cell Proliferation Cell model Cells Cellular Metabolic Process Cessation of life Cholecalciferol Chromosomes Clinical Colorectal Computer Assisted Consumption DNA DNA Binding Development Diagnosis Differentiation and Growth Disease Drug Design Early Diagnosis Elderly Electron Transport Enzyme-Linked Immunosorbent Assay Epithelial Estrogen Receptor alpha Estrogen Receptors Exhibits Female Breast Carcinoma Funding Gene Expression General Population Genes Glycolysis Goals Growth Head and Neck Cancer Health Healthcare Healthcare Systems Hormones Laboratories Lactate Dehydrogenase Lipids Lung Male mammary gland Malignant Neoplasms Malignant neoplasm of male breast Measures Mediating Mediator of activation protein Mesenchymal Metabolic Metabolic Pathway Metabolism Metastatic breast cancer Methods Mission Mitochondria Molecular Molecular Weight Morbidity - disease rate Morphology Mortality Decline Neoplasm Metastasis Normal Cell Nutritional Oncogenes Oncogenic Oxidative Phosphorylation Oxides Oxidoreductase Oxygen Oxygen Consumption Pathology Pathway interactions Patient Care Patients Phenotype Phosphorylation Population Preclinical Drug Evaluation Primary Neoplasm Private Sector Proliferating Proteins Pyruvate Metabolism Pathway Receptor Cell Regulation Respiration Risk Factors Site Smoker Smoking Subgroup Suppressor Genes System Testing Therapeutic Therapeutic Intervention Thyroid Gland Time Transcriptional Regulation Treatment Efficacy United States United States Department of Veterans Affairs Variant Vascular Diseases Veterans Vitamin D Warburg Effect Woman aerobic glycolysis bone cell growth cell transformation clinically relevant design effective therapy glucose metabolism in vivo insight malignant breast neoplasm melanoma men mortality neoplastic cell new therapeutic target novel novel therapeutics osteosarcoma outcome forecast overexpression prevent prohormone public health relevance therapeutic target transcription factor tumor tumor growth tumor metabolism tumor progression

项目摘要

DESCRIPTION (provided by applicant): Breast cancer (BC) continues to be the most common cancer in women and is responsible for almost 40,000 deaths per year. According to the VA Center for Women Veterans, women are the fastest growing subgroup of U.S. veterans and this number is expected to grow in the next 10 years. Therefore, as the population ages, VA health care will be in high demand by women veterans. This is because some of the same risk factors that are associated with poor prognosis in the general population are also found in the VA population. The VA also treats a moderately high volume of male BC and, unlike the declining mortality for female BC, death rates from male BC have not decreased. Compared with the general population, a higher proportion of the male and female BC patients in the VA system are African-American, relative to the private sector, and this population exhibits higher mortality and morbidity rates. Therefore, identifying effective therapeutic targets to treat these diverse groups of veterans is highly relevant to the VA patient care mission. The previous VA Merit funded project addressed questions about how breast cancers acquire hormone independence and become metastatic or spread throughout the body. We suspected that this type of tumor progression was controlled by a BC protein (RUNX2) that regulates expression of genes that promote growth and metastasis. We also proposed to discover compounds that would inhibit the ability of this factor to increase BC progression. We found that the RUNX2 factor promotes BC progression to a more aggressive, metastatic form by increasing glucose metabolism, inhibiting mitochondrial respiration, and reducing epithelial- specific gene expression, or differentiation. We also used novel drug screening methods and activity assays developed in the laboratory to characterize several compounds related to vitamin D that inhibited the RUNX2 factor and BC growth. Given these observations, in this VA Merit renewal application we propose the hypothesis that the RUNX2 factor can alter BC metabolism and inhibit cell differentiation while promoting tumor progression. We further propose that targeted inhibition of this factor using novel vitamin D derivatives will restore normal cell metabolism and differentiation, prevent further tumor progression, and inhibit BC growth. The goal of this proposal, therefore, is to perform a comprehensive but focused analysis of the relationship between RUNX2-mediated breast cancer growth and differentiation. RUNX2 may promote a metabolic progression favoring glycolysis and suppressing mitochondrial respiration. Several specific BC cell models and novel compounds that promote BC cell differentiation will be used to define the mechanisms regulating breast cancer progression and metastasis. The goals are to (1) define the RUNX2-regulated relationship between BC cell differentiation, metabolism, and progression, (2) define how Vitamin D3 prohormone regulates RUNX2 DNA binding and BC differentiation through its regulation of cell metabolism, and (3) determine the mechanisms regulating RUNX2 DNA binding and BC differentiation by oxidized variants of Vitamin D3. Many patients within the Veterans Administration health care system also suffer from lung, colorectal, and head/neck cancers, which are prevalent in elderly veterans who are smokers. Our study may provide insight into understanding the molecular pathways regulating these malignancies. Because the hypotheses we are testing are also relevant to how RUNX2 regulates vascular disease, therapeutic targeting strategies discovered in this study may have applicability and clinical relevance for other pathologies prevalent in the veteran population that are exacerbated by aging and smoking, such as cardiovascular disease. !

描述(由申请人提供)：乳腺癌(BC)仍然是女性最常见的癌症，每年导致近40,000人死亡。根据退伍军人女性中心的数据，女性是美国退伍军人中增长最快的亚群体，这一数字预计在未来10年内还会增长。因此，随着人口老龄化，退伍军人对退伍军人的医疗保健需求将会很高。这是因为在退伍军人中也发现了一些与普通人群预后不良相关的危险因素。退伍军人管理局还治疗中等数量的男性BC，与女性BC死亡率下降不同的是，男性BC的死亡率并没有下降。与普通人群相比，退伍军人管理局系统中的男性和女性BC患者中非洲裔美国人的比例高于私营部门，这一群体表现出更高的死亡率和发病率。因此，识别有效的治疗这些不同的退伍军人群体的治疗目标与退伍军人管理局的患者护理任务高度相关。之前的VA Merit资助的项目解决了乳腺癌如何获得激素独立性并成为转移或扩散到全身的问题。我们怀疑这种类型的肿瘤进展是由一种BC蛋白(RUNX2)控制的，该蛋白调节促进生长和转移的基因的表达。我们还建议发现一些化合物，可以抑制该因子促进BC进展的能力。我们发现，RUNX2因子通过增加葡萄糖代谢，抑制线粒体呼吸，减少上皮细胞特异性基因表达，或减少分化，促进BC进展到更具侵袭性的转移形式。我们还使用了新的药物筛选方法和实验室开发的活性分析来表征几种与维生素D相关的化合物，这些化合物可以抑制RUNX2因子和BC的生长。鉴于这些观察，在VA Merit更新应用中，我们提出了假设，即RUNX2因子可以改变BC代谢并抑制细胞分化，同时促进肿瘤进展。我们进一步提出，使用新的维生素D衍生物靶向抑制该因子将恢复正常的细胞代谢和分化，防止肿瘤进一步发展，并抑制BC生长。因此，这项建议的目标是对RUNX2介导的乳腺癌生长和分化之间的关系进行全面而集中的分析。Runx2可能促进代谢进程，有利于糖酵解和抑制线粒体呼吸。一些特定的BC细胞模型和促进BC细胞分化的新化合物将被用来确定调控乳腺癌进展和转移的机制。其目的是(1)确定RUNX2调控的BC细胞分化、代谢和进展之间的关系，(2)确定维生素D3前激素如何通过调节细胞代谢来调节RUNX2 DNA结合和BC分化，以及(3)确定维生素D3的氧化变体调控RUNX2 DNA结合和BC分化的机制。退伍军人管理局医疗保健系统中的许多患者还患有肺癌、结直肠癌和头颈癌，这些癌症在吸烟的老年退伍军人中很常见。我们的研究可能为理解调控这些恶性肿瘤的分子途径提供洞察力。由于我们正在测试的假设也与RUNX2如何调节血管疾病有关，因此本研究中发现的治疗靶向策略可能对退伍军人中流行的其他病理具有适用性和临床相关性衰老和吸烟，如心血管疾病，会加剧这种疾病。好了！