A novel strategy to debilitate breast cancer metastasis

削弱乳腺癌转移的新策略

• 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
• 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

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.

摘要 缺氧是影响肿瘤进展和转移的关键微环境因素之一， 实体瘤如乳腺癌。在评估缺氧的影响时，我们的团队进行了一次意想不到的 但令人惊讶的是，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，这种增加是伴随着核仁的活性上调。在 RNA Pol I转录rDNA（包含18S、5.8S和28S rRNA序列）以驱动核糖体 生物起源。我们认为，这种增加的核糖体生物合成是缺氧细胞存活所必需的， 随后的疾病进展。在缺氧反应中，核仁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激活因子， 激活RNA Pol I。我们认为，这种核仁活性的增加是缺氧肿瘤细胞的脆弱性。 我们的目标是测试一种方法，利用依赖于ERK激活的缺氧乳腺癌细胞。 我们认为，低氧应激后核仁ERK激活后rRNA生物合成的减弱， 显著抑制乳腺癌细胞的肿瘤生长和转移扩散。为了验证这一点，我们将采用 精心设计的细胞和动物实验方法，以测试拮抗ERK和RNA的效果， Pol I活性对转移进展的影响。此外，我们将确定核仁ERK的机制细节， 功能协调发展的总之，我们的工作将揭示肿瘤细胞核仁ERK反应的新方面，支持其对肿瘤细胞的作用。 在缺氧条件下的存活和转移能力。