A novel strategy to debilitate breast cancer metastasis

削弱乳腺癌转移的新策略

基本信息

批准号：
10508990
负责人：
Rajeev S Samant
金额：
$ 7.43万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10508990
关键词：
Adopted Animals Binding Biogenesis Breast Cancer Cell Breast cancer metastasis Cell Hypoxia Cell Nucleolus Cell Survival Cells Chronic Dependence Disease Disease Progression Dominant-Negative Mutation Drug resistance Ensure Event Extracellular Signal Regulated Kinases FDA approved Genetic Transcription Homeostasis Hypoxia Hypoxia Inducible Factor In Vitro Intuition Licensing Factor Literature Maintenance Malignant Neoplasms Mammary Neoplasms Messenger RNA Metastatic breast cancer Neoplasm Metastasis Outcome Oxygen Process Prognosis Proliferating Proteins Proteome Publications Publishing RNA Polymerase I RNA, Ribosomal, 28S Reaction Research Project Grants Resistance Ribosomal DNA Ribosomal Proteins Ribosomal RNA Ribosomes Signal Transduction Site Solid Neoplasm Stress Supporting Cell Testing Transcription Coactivator Translating Translations Tumor Tissue Work base biological adaptation to stress breast cancer progression cancer cell cancer survival design experience in vivo innovation kinase inhibitor malignant breast neoplasm neoplastic cell novel novel strategies pre-clinical programs response sound stressor therapeutic target therapy resistant tool transcription factor tumor tumor growth tumor hypoxia tumor progression

项目摘要

Abstract Hypoxia is one of the key microenvironmental factors that impinges upon tumor progression and metastasis of solid tumors such as breast cancer. While evaluating the impact of hypoxia, our group made an unanticipated but striking observation that in chronic hypoxia, mammary tumors display a remarkable increase in the number of nucleoli per cell. We found that this increase is concomitant with upregulated activity of the nucleolus. In the nucleolus, RNA Pol I transcribes rDNA (contains the sequences of 18S, 5.8S and 28S rRNAs) to drive ribosome biogenesis. We contend that this increased ribosome biogenesis is essential for hypoxic cell survival and subsequent disease progression. In response to hypoxia, nucleolar ERK signaling activity is increased. Increased ERK directly impinges upon the activity of UBF, a nucleolus-specific transcription activator, which activates RNA Pol I. We contend that this increased nucleolar activity is a vulnerability of hypoxic tumor cells. Our objective is to test an approach to exploit the dependence of hypoxic breast cancer cells on ERK activation. We contend that debilitating the rRNA biogenesis following nucleolar ERK activation following hypoxic stress will remarkably restrict the tumor growth and metastatic spread of breast cancer cells. To test this, we will adopt carefully designed cellular and animal experimental approaches to test the effect of antagonizing ERK and RNA Pol I activity on metastatic progression. Additionally, we will identify mechanistic details of nucleolar ERK functions. Overall, our work will reveal novel aspects of nucleolar ERK response of tumor cells that support their survival and metastatic ability under hypoxia.

抽象的缺氧是影响肿瘤进展和转移的关键微环境因素之一实体瘤，例如乳腺癌。在评估缺氧的影响的同时，我们的小组做出了意想不到的但是惊人的观察结果是，在慢性缺氧中，乳腺肿瘤的数量显着增加每个细胞的核仁。我们发现，这种增加与核仁的上调活性同时。在 Nucleolus，RNA Pol I转录rDNA（包含18s，5.8s和28s rRNA的序列）以驱动核糖体生物发生。我们认为，这种增加的核糖体生物发生对于低氧细胞存活和随后的疾病进展。响应缺氧，核糖ERK信号传导活性增加。 ERK的增加直接影响UBF的活性，UBF是一种核仁特异性转录活化剂，该活化剂，该活化剂激活RNA polI。我们认为这种增加的核仁活性是低氧肿瘤细胞的脆弱性。我们的目标是测试一种利用低氧乳腺癌细胞对ERK激活的依赖性的方法。我们认为，在低氧应激之后核仁ERK激活后rRNA生物发生衰弱明显限制了乳腺癌细胞的肿瘤生长和转移性扩散。为了测试这一点，我们将采用精心设计的细胞和动物实验方法测试拮抗ERK和RNA的效果 pol I活性在转移性进程上。此外，我们将确定核仁ERK的机理细节功能。总体而言，我们的工作将揭示肿瘤细胞的核仁ERK反应的新方面在缺氧下的生存和转移能力。