Runx2 Organizes Transcriptional Complexes in Nuclear Microenvironments to Support

主转录调节因子Runx 2是骨生成所必需的，具有多功能的分子生物学功能。 和生物学。Runx 2是一种支架蛋白，与不同的共调节因子相互作用， 并且通过独特的Runx 2核基质靶向信号靶向亚核结构域。Runx 2是一款高性能 在转移到骨的肿瘤细胞中表达，在非转移性恶性细胞中以痕量水平存在 并且在正常乳腺上皮细胞中几乎不存在。我们已经证明了独特的靶向功能 Runx 2的表达是其促进骨中肿瘤生长和溶骨性骨病的活性所必需的。 我们已经证明Runx 2是许多基因的转录激活因子，这些基因参与了早期和晚期的细胞凋亡事件。 转移和介导有助于肿瘤生长的信号传导途径。因此，我们假设 Runx 2在高转移性乳腺癌中调节一组异常激活或抑制的基因， 乳腺肿瘤细胞的亚核区域中的癌细胞，其将促进向远端的转移 网站.重要的是，我们已经确定肿瘤细胞中Runx 2基底膜的缺失（通过Runx 2 shRNA和一种新的表达载体）， 亚核靶向缺陷（STD）突变）减少乳腺中的肿瘤生长并阻断 转移性骨病因此，我们建议进一步了解Runx 2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Runx 2促进乳腺癌细胞从乳腺癌细胞转移。 原发性乳腺肿瘤和核微环境中Runx 2的破坏将减少 2-表征特异性Runx 2皮下依赖性转移事件; 乳腺脂肪垫和骨微环境中肿瘤生长所需的功能;以及 乳腺癌细胞亚核结构域中支持肿瘤生长的特异性调节蛋白的鉴定 生长和转移。这些研究与项目1和项目2合作，将Runx 2定义为主体 通过鉴定新的Runx 2依赖性信号通路， 在核微环境中发挥作用，并促进乳腺癌的进展。 相关性（见说明）： Runx 2在前列腺癌和乳腺癌患者中被激活并随着疾病的严重程度而增加。 失活这个调控许多转移相关基因的主转录因子，可以防止 肿瘤生长在骨中，这是一个对患者预后不良的疾病阶段。通过调查 Runx 2在乳腺肿瘤亚核病灶中的功能活性，我们将深入了解新的 肿瘤远端转移的免疫抑制机制 项目/生产现场（如果需要额外空间，请使用项目/生产现场表格页） 项目/执行地点主要位置 组织名称：马萨诸塞州大学医学院 电话：603847393 streeti：55 Lake Avenue North street 2： 城市：Worcester County：州：MA 邮政编码：01566 项目/演出地点国会区：MA-003 其他项目/业绩

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