Runx2 Organizes Transcriptional Complexes in Nuclear Microenvironments to Support

Runx2 在核微环境中组织转录复合物以支持

• 批准号: 8052327
• 负责人: Jane B. Lian
• 金额: $ 28.48万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052327
• 关键词: Biochemical; Biological; Bone Diseases; Bone Matrix; Breast; Breast Cancer Cell; Cancer Patient; Cell Nucleus; Cells; Cities; Code; Collaborations; Complementary DNA; Complex; Country; County; Coupled; Disease; Disease Progression; Distal; Epithelial Cells; Erinaceidae; Event; Fatty acid glycerol esters; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Human; In Situ; In Vitro; Integrins; Lead; Location; MCF7 cell; Malignant neoplasm of prostate; Mammary Neoplasms; Mammary gland; Massachusetts; Mediating; Mediator of activation protein; Metalloproteases; Metastatic Neoplasm to the Bone; Molecular; Molecular Profiling; Mouse Mammary Tumor Virus; Mutation; Names; Neoplasm Metastasis; Non-Malignant; Normal Cell; Nuclear; Nuclear Matrix; Nuclear Matrix-Associated Proteins; Nuclear Structure; Oncogenic; Osteogenesis; Osteolytic; Outcome; Patients; Performance; Polyomavirus; Property; Prostatic Neoplasms; Proteins; Proteomics; Province; Runx2 protein; Sampling; Scaffolding Protein; Severity of illness; Signal Pathway; Signal Transduction; Site; Staging; Supporting Cell; Transcription Coactivator; Universities; Vascular Endothelial Growth Factors; Viral Tumor Antigens; Work; bone; cancer cell; cohort; genetic regulatory protein; insight; inter-alpha-inhibitor; malignant breast neoplasm; medical schools; mouse model; mutant; neoplastic cell; novel; parathyroid hormone-related protein; prevent; response; transcription factor; tumor; tumor growth; validation studies

The master transcriptional regulator Runx2 is essential for osteogenesis and has multifunctional molecular and biological. Runx2 is properties as a scaffolding protein that interacts with distinct co-regulatory factors and is targeted by a unique Runx2 nuclear matrix targeting signal to subnuclear domains. Runx2 is highly expressed in tumor cells that metastasize to bone, present at trace levels in non-metastatic malignant cells and nearly absent from normal mammary epithelial cells. We have proven thatthe unique targeting function of Runx2 is an essential for its activity which promotes tumor growth in bone and osteolytic bone disease. We have shown that Runx2 is a transcriptional activator of many genes involved in early and late events of metastasis and mediates signaling pathways that contribute to tumor growth. Therefore, we hypothesize that Runx2 regulates a cohort of genes abnormally activated or repressed genes in highly metastatic breast cancer cells in subnuclear domains of tumor cells in mammary gland that will promote metastasis to distal sites. Importantly, we have established that loss of Runx2 fundion in tumor cells (by Runx2 shRNAs and a subnuclear targeting deficient (STD) mutation) reduces tumor growth in the mammary gland and blocks metastatic bone disease. Thus, we propose to further understand the mechanisms of Runx2 activities that are responsive to the mammary tumor microenvironment and are aberrantly associated with subnuclear foci in tumor cells. Our aims are to 1- Establish that Runx2 promotes metastasis of breast cancer cells from primary mammary tumors and that disruption of Runx2 in nuclear microenvironments will deaease metastatic events in a genetic mouse model; 2- Characterize the specific Runx2 subnudear-dependent functions that are required for tumor growth in the mammary fat pad and the bone microenvironment; and 3- Identify specific regulatory proteins in subnuclear domains of breast cancer cells that support to tumor growth and metastasis. These studies, in collaboration with Projects 1 and 2, will define Runx2 as a principal mediator of tumor growth and metastasis by identifying novel Runx2-dependent signaling pathways which function in nuclear microenvironments and contribute to progression of breast cancer. RELEVANCE (See instmctions): Runx2 is activated and increases with severity of disease in prostate and breast cancers patients. Inactivation of this master transcription factor that regulates many metastasis related genes, can prevent tumor growth in bone, a stage ofthe disease having a poor outcome for patients. By investigating the functional activities of Runx2 in subnuclear foci in mammary tumors, we will gain insight into novel mechanisms nnfirativfi diirinn tumor nrnnrflssinn and In nromotinn metastasis to distal sites PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Perfomiance Site Fomiat Page) Project/Perfonnance Site Primary Location Organizational Name: University of Massachusetts Medical School DUNS: 603847393 streeti: 55 Lake Avenue North street 2: City: Worcester County: State: MA Province: Country: USA Zip/Postal Code: 01566 Project/Perfonnance Site Congressional Districts: MA-003 Additional Project/Performance

主转录调节因子 Runx2 对于成骨至关重要，具有多功能分子 和生物。 Runx2 具有作为支架蛋白的特性，可与不同的共同调节因子相互作用 并被独特的 Runx2 核基质靶向亚核域信号所靶向。 Runx2 高度 在转移至骨的肿瘤细胞中表达，在非转移性恶性细胞中以微量水平存在 正常乳腺上皮细胞中几乎不存在。我们已经证明独特的定位功能 Runx2 对其促进骨肿瘤生长和溶骨性骨疾病的活性至关重要。 我们已经证明 Runx2 是参与早期和晚期事件的许多基因的转录激活因子 转移并介导有助于肿瘤生长的信号通路。因此，我们假设 Runx2 调节高度转移性乳腺中异常激活或抑制的一组基因 乳腺肿瘤细胞亚核域中的癌细胞会促进远端转移 网站。重要的是，我们已经确定肿瘤细胞中 Runx2 功能的丧失（通过 Runx2 shRNA 和 亚核靶向缺陷（STD）突变）可减少乳腺中的肿瘤生长并阻止 转移性骨病。因此，我们建议进一步了解 Runx2 活动的机制 对乳腺肿瘤微环境有反应，并与亚核病灶异常相关 在肿瘤细胞中。我们的目标是 1- 确定 Runx2 促进乳腺癌细胞的转移 原发性乳腺肿瘤以及核微环境中 Runx2 的破坏将会缓解 遗传小鼠模型中的转移事件； 2-表征特定的 Runx2 subnudear-dependent 乳腺脂肪垫和骨微环境中肿瘤生长所需的功能；和 3- 鉴定乳腺癌细胞亚核域中支持肿瘤的特定调节蛋白 生长和转移。这些研究与项目 1 和 2 合作，将 Runx2 定义为主要的 通过识别新的 Runx2 依赖性信号通路来调节肿瘤生长和转移 在核微环境中发挥作用并有助于乳腺癌的进展。 相关性（参见说明）： Runx2 在前列腺癌和乳腺癌患者中随着疾病的严重程度而被激活并增加。 这种调节许多转移相关基因的主转录因子失活可以预防 肿瘤在骨中生长，这是疾病的一个阶段，对患者来说预后不佳。通过调查 Runx2 在乳腺肿瘤亚核灶中的功能活动，我们将深入了解新的 肿瘤转移至远端部位的机制 项目/绩效网站（如果需要额外空间，请使用项目/绩效网站信息页面） 项目/绩效地点 主要地点 组织名称：马萨诸塞大学医学院 邓氏编码：603847393 streeti: 55 Lake Avenue North street 2: 城市： 伍斯特县： 州： MA 省份： 国家： 美国 邮政编码： 01566 项目/性能地点国会选区：MA-003 额外的项目/表演