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; 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

主转录调节器Runx2对于成骨作用至关重要，具有多功能分子 和生物学。 runx2是一种脚手架蛋白的性能，与不同的共调节因子相互作用 并由唯一的Runx2核基质靶向信号对亚核域的靶向。 runx2是高度的 在转移到骨的肿瘤细胞中，在非转移性恶性细胞中的痕量水平上表达 几乎没有正常乳腺上皮细胞。我们已经证明了独特的目标功能 Runx2的活性是促进骨骼和骨骨病的肿瘤生长的必不可少的。 我们已经表明，Runx2是许多与早期和晚期事件有关的基因的转录激活因子 转移和介导导致肿瘤生长的信号通路。因此，我们假设 Runx2调节高度转移性乳房中的基因异常激活或抑制基因 乳腺肿瘤细胞亚核域中的癌细胞，将促进转移至远端 站点。重要的是，我们已经确定了肿瘤细胞中Runx2 Fultion的损失（runx2 shrnas和a 亚核靶向缺陷（STD）突变）减少了乳腺的肿瘤生长和阻滞 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，与亚核灶异常相关 在肿瘤细胞中。我们的目的是1-确定Runx2促进了乳腺癌细胞的转移 原发性乳腺肿瘤和核微环境中RUNX2的破坏将使 遗传小鼠模型中的转移事件； 2-表征特定的runx2 subnudear依赖性 乳腺脂肪垫和骨微环境中肿瘤生长所需的功能；和3- 在乳腺癌细胞的亚核域中确定特定的调节蛋白，以支持肿瘤 生长和转移。这些研究与项目1和2合作将把Runx2定义为主要 肿瘤生长和转移的介体通过鉴定新的Runx2依赖性信号通路，这些途径 在核微环境中的功能并有助于乳腺癌的发展。 相关性（请参阅Instmctions）： Runx2被激活，并随着前列腺和乳腺癌患者的疾病严重程度而增加。 调节许多相关基因的主转录因子的失活，可以防止 骨骼中的肿瘤生长是该疾病的阶段，患者的预后较差。通过调查 Runx2在乳腺肿瘤亚核灶中的功能活性，我们将深入了解新型 机制Nnfirativfi diirinn肿瘤nrnnrflssinn以及nromotinn转移到远端位点 项目/穿越稳定站点（如果需要额外的空间，请使用Project/Perfomance网站Fomiat页面） 项目/完美网站的主要位置 组织名称：马萨诸塞大学医学院 Duns：603847393 Streeti：55 Lake Avenue North Street 2： 城市：伍斯特县：州：马萨诸塞州 省：国家/地区：美国邮政编码/邮政代码：01566 项目/完美场地国会区：MA-003 附加项目/性能