Runx2 Organizes Transcriptional Complexes in Nuclear Microenvironments to Support

主要转录调控因子Runx2是成骨所必需的，具有多功能分子 和生物学上的。Runx2是一种支架蛋白，与不同的协同调节因子相互作用 并被一种独特的Runx2核基质靶向于亚核结构域。Runx2高度 在转移到骨的肿瘤细胞中表达，在非转移性恶性细胞中存在微量水平 在正常乳腺上皮细胞中几乎不存在。我们已经证明，独特的靶向功能 Runx2的活性是促进骨肿瘤生长和溶骨性骨病所必需的。 我们已经证明，Runx2是许多基因的转录激活因子，涉及早期和晚期事件。 转移，并介导有助于肿瘤生长的信号通路。因此，我们假设 Runx2基因在高转移乳腺中调节一组异常激活或抑制的基因 乳腺癌细胞亚核区内的癌细胞可促进远处转移 网站。重要的是，我们已经确定了肿瘤细胞中Runx2功能子的丢失(通过Runx2 shRNAs和a 亚核靶向缺陷(STD)突变)减少乳腺肿瘤生长并阻断 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，并与核下病灶异常相关 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。 原发乳腺肿瘤和核微环境中Runx2的破坏将会导致死亡 遗传性小鼠模型中的转移事件；2-表征特定的Runx2亚核依赖 乳腺脂肪垫和骨骼微环境中肿瘤生长所需的功能；以及3- 确定乳腺癌细胞亚核结构域中支持肿瘤的特异性调控蛋白 生长和转移。这些研究将与项目1和项目2合作，将Runx2定义为主体 通过识别新的依赖Runx2的信号通路来调节肿瘤的生长和转移 在核微环境中发挥作用，并促进乳腺癌的进展。 相关性(请参阅说明)： 在前列腺癌和乳腺癌患者中，Runx2被激活，并随着疾病的严重程度而增加。 这个调节许多转移相关基因的主要转录因子的失活可以防止 肿瘤在骨中生长，这是疾病的一个阶段，患者的预后很差。通过调查 Runx2在乳腺肿瘤核下局灶区的功能活性，我们将洞察新的 肿瘤转移及转移到远端的机制 项目/绩效网站(S)(如果需要额外空间，请使用项目/绩效网站格式页面) 项目/绩效站点主要位置 组织名称：马萨诸塞大学医学院 邓斯：603847393 Streeti：湖大道55号北街2号： 城市：伍斯特县：州：马州 省：国家：美国邮政编码：01566 项目/表演场地国会地区：MA-003 其他项目/绩效

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