Transcriptional Regulation of Breast Cancer Metastasis within the Tumor Microenvi

肿瘤微环境中乳腺癌转移的转录调控

• 批准号: 8919859
• 负责人: Clayton Yates
• 金额: $ 19.43万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919859
• 关键词: Animal Model; Animals; Basic Science; Behavior; Binding; Bioreactors; Breast Cancer Cell; Breast Cancer cell line; Breast Carcinoma; Breast cancer metastasis; Cell Nucleus; Cells; Chills; CpG Islands; Cytoplasm; Cytosol; DNA; DNA Methylation; DNA Structure; Data; Development; Down-Regulation; Drug Design; E-Cadherin; ERBB2 gene; Environment; Epidermal Growth Factor Receptor; Epithelial; Family; Family member; Figs - dietary; Future; Genetic Engineering; Health; Human; Link; Liver; Malignant Epithelial Cell; Mediating; Membrane; Mesenchymal; Methylation; Modeling; Molecular; Movement; Neoplasm Metastasis; Nuclear; Organ; Phenotype; Positioning Attribute; Primary Neoplasm; Property; Receptor Signaling; Role; Signal Transduction; Site; Testing; Transcription Repressor/Corepressor; Transcriptional Regulation; Tumor Biology; autocrine; base; cellular engineering; innovation; insight; malignant breast neoplasm; mortality; novel; receptor; receptor binding; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Breast carcinoma escape from the primary site leads to mortality. Recently, it has been found that tumor properties of aggressiveness required for dissemination may revert within metastatic microenvironment to enable seeding, in part through reversal of methylation of E-cadherin. The initial mesenchymal transition that allows breast cancer cells to disseminate from the primary tumor is driven via EGFR family signaling (HER1 and HER2). However, during metastatic seeding, EGFR family signaling is downregulated and E-cadherin is re-expressed. We present preliminary data showing that downregulation of Kaiso, or restricting Kaiso from the nucleus, drives breast cancer cells towards a differentiated epithelial-like phenotype. Thus, our novel foundational model of metastatic seeding posits a key molecular link that enables the breast carcinoma cells to incorporate into the ectopic environment and even become dormant, that of retaining Kaiso out of the nucleus so that E-cadherin can be re-expressed. In this proposal we will establish that both metastatic seeding and tumor dormancy can be minimized if not eliminated by modulating this molecular cascade. The aims to be tested are Specific Aim 1. Determine how EGF receptor signaling causes relocalization of Kaiso into the nucleus and whether this alters DNA methylation and the carcinoma cell phenotype. In this aim, we will 1) Determine the influence of autocrine EGFR signaling on Kaiso localization/expression and methylation status of E-cadherin in breast cancer, and 2) Determine breast cancer phenotype upon sequestration of Kaiso outside of the nucleus, using pharmacological and molecular constructs, and 3) Determine how EGF receptor signaling/cascade coordinately alters Kaiso subcellular localization and DNA methylation in breast cancer cell lines. Specific Aim 2. 1) Determine whether disruption of Kaiso relocalization into the nucleus alters entry into the metastatic niche and/or the development of tumor dormancy. We will introduce the carcinoma cells into the bioreactor and determine the localization of Kaiso along with the expression of E-cadherin during initial metastatic seeding. 2) Determine the influence of sequestering Kaiso localization outside of the nucleus on tumor dormancy within the organotypic liver microenvironment. 3) Determine the role of nuclear Kaiso on the two steps of escape from the primary tumor and seeding of the metastatic microenvironment in animals. In summary, through the use of primary human explants, established lines, and an innovative human organotypic liver bioreactor as well as animal models, we will determine Kaiso localization and expression levels and that correlate with cell phenotype and cellular behaviors with the tumor microenvironment. Successful completion of these studies would could have immediate impact be on the basic science of tumor biology, and provide paradigm shifting insights into the molecular mechanisms by which breast carcinomas metastasize and enter dormancy, one of the most chilling aspects of progression.

描述（由申请人提供）：乳腺癌从主要部位逃脱会导致死亡率。最近，已经发现，传播所需的攻击性肿瘤特性可能会恢复转移性微环境内的肿瘤特性，以部分通过E-钙粘着蛋白的甲基化逆转来使播种。允许乳腺癌细胞从原发性肿瘤传播的最初的间充质转变是通过EGFR家族信号传导（HER1和HER2）驱动的。但是，在转移播种期间，EGFR家族信号被下调，E-钙粘蛋白被重新表达。我们提供了初步数据，表明Kaiso的下调或限制了核中的Kaiso，将乳腺癌细胞驱动到分化的上皮表型。因此，我们的新型转移播种基础模型提出了一个关键的分子环，使乳腺癌细胞能够纳入异位环境，甚至处于休眠状态，从而将Kaiso从细胞核中保留出来，从而可以重新表达E-钙粘蛋白。在此提案中，我们将确定，如果不能通过调节该分子级联反应来消除转移性播种和肿瘤休眠。要测试的目的是特定的目标1。确定EGF受体信号如何导致Kaiso重新定位到核中，以及该如何改变DNA甲基化和癌细胞表型。在此目的中，我们将1）确定自分泌EGFR信号对乳腺癌中电子钙粘着蛋白的Kaiso定位/表达和甲基化状态的影响，2）使用药理和药理学和药理学和分子构建体和3）确定EGF受体信号传导/级联如何协调地改变乳腺癌细胞系中的Kaiso亚细胞定位和DNA甲基化。具体目的2。1）确定kaiso重新定位到核中的破坏是否会改变进入转移性细分市场和/或肿瘤休眠的发展。我们将将癌细胞引入生物反应器，并确定Kaiso的定位以及在初始转移播种期间E-钙粘着蛋白的表达。 2） 确定在细胞核外部隔离的Kaiso定位对器官肝微环境内肿瘤休眠状态的影响。 3）确定核kaiso在逃离原发性肿瘤的两个步骤和动物转移微环境的播种方面的作用。总而言之，通过使用原代人类外植体，建立的线条以及创新的人体肝脏生物反应器以及动物模型，我们将确定Kaiso定位和表达水平，并与细胞表型和细胞表型和肿瘤微环境相关。这些研究的成功完成可能会立即对肿瘤生物学的基础科学产生影响，并为乳腺癌转移并进入宿舍的分子机制提供范式转移见解，这是进展最令人寒冷的方面之一。