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，每年造成近40,000人死亡。根据VA妇女退伍军人中心的说法，妇女是美国退伍军人增长最快的亚组，预计未来10年的数字将增长。因此，随着人口年龄的增长，VA医疗保健的需求量很高。这是因为在VA人群中也发现了一些与普通人群不良预后相同的危险因素。 VA还可以治疗中等程度的男性BC，与女性BC死亡率下降不同，男性卑诗省的死亡率尚未降低。与普通人群相比，VA系统中的男性和女性BC患者比例更高，相对于私营部门，该人群的死亡率和发病率更高。因此，确定有效治疗这些不同的退伍军人群体的治疗目标与VA患者护理任务高度相关。先前的VA优点资助的项目解决了有关乳腺癌如何获得激素独立性并在整个身体中传播或扩散的问题。我们怀疑这种类型的肿瘤进展由BC蛋白（Runx2）控制，该蛋白调节促进生长和转移的基因的表达。我们还建议发现可以抑制该因素增加BC进展能力的化合物。我们发现，Runx2因子通过增加葡萄糖代谢，抑制线粒体呼吸并减少上皮 - 特异性基因表达或分化，从而促进了BC的进展到更具侵略性的转移形式。我们还使用了在实验室开发的新型药物筛查方法和活性测定法，以表征与抑制Runx2因子和BC生长的维生素D相关的几种化合物。鉴于这些观察结果，在此VA值得更新应用中，我们提出了一个假设，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，使用新型维生素D衍生物靶向抑制该因子将恢复正常的细胞代谢和分化，防止进一步的肿瘤进展并抑制BC的生长。因此，该提案的目的是对Runx2介导的乳腺癌生长与分化之间的关系进行全面但专注的分析。 RUNX2可能会促进有利于糖酵解和抑制线粒体呼吸的代谢进展。促进BC细胞分化的几种特定BC细胞模型和新型化合物将用于定义调节乳腺癌进展和转移的机制。目标是（1）定义BC细胞分化，代谢和进展之间的RUNX2调节关系，（2）定义维生素D3促态如何调节RUNX2 DNA结合和BC通过调节细胞代谢的调节，并通过其对细胞代谢的调控，（3）确定contrizations bc Adigiant dna Bcatization dna dna dna dna的机制。退伍军人管理系统中的许多患者也患有肺，结直肠和头颈癌，这些患者在吸烟者的老年退伍军人中很普遍。我们的研究可能会洞悉了解调节这些恶性肿瘤的分子途径。由于我们正在测试的假设也与RUNX2调节血管疾病有关因衰老和吸烟而加剧，例如心血管疾病。呢