MTA1 IN ONCOGENESIS

MTA1 在肿瘤发生中的作用

• 批准号: 7769279
• 负责人: Rakesh Kumar
• 金额: $ 28万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769279
• 关键词: Acetylation; Address; Aggressive Clinical Course; Breast; Breast Cancer Cell; Cells; Cessation of life; Characteristics; Chromatin; Chromatin Remodeling Factor; Data; Development; Disease-Free Survival; Epithelial Cells; Genes; Gi2-alpha protein; Growth; Human; Knowledge; Laboratories; Link; Lysine; Malignant Neoplasms; Malignant neoplasm of lung; Mammary Neoplasms; Mammary gland; Metastatic Neoplasm to the Lung; Molecular; Molecular Target; Mus; Neoplasm Metastasis; Neurons; Nodule; NuRD complex; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Physiological; Play; Primary Neoplasm; Property; Protein Overexpression; Proteins; Ras Inhibitor; Rate; Regulation; Regulatory Pathway; Research; Role; Signal Transduction; Site; Specimen; Time; Tumor Antigens; Up-Regulation; Woman; Work; base; brain cell; cancer cell; design; follow-up; inhibitor/antagonist; innovation; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Breast cancer is the leading site of new cancer cases in women and is the second leading cause (after lung cancer) of cancer death among women. The high mortality rate associated with breast cancer, however, is due to a propensity for these tumors to spread while the primary tumors are small and undetected. The molecular mechanisms underlying the upstream regulation of the Wnt1 and STAT3, two major transforming molecules in human cancer and, in turn, progression and metastasis of these cancers are not completely understood at the present time, but believed to involve perturbation of master chromatin modifiers. For example, overexpression of metastatic tumor antigen 1 (MTA1), a master chromatin modifier, is frequently associated with an aggressive clinical course in human breast cancer. Despite the remarkable growth of information about MTA1, Wnt1, and STAT3, knowledge regarding the mechanism by which MTA1 and the direct targets of MTA1-containing coregulatory complexes regulate mammary epithelial cell transformation and metastasis remains elusive, and is the focus of this application. In this context, our recent work suggests that MTA1 deregulation in mammary epithelial cells plays a significant role in stimulating Wnt1 via targeting of specific gene chromatin, namely repressing Six3 (a direct corepressor of Wnt1), and STAT3 chromatin. In addition, for the first time, we discovered that MTA1 is required for breast-to-lung metastasis in a transgenic mouse model. This proposal is designed to establish the mechanism by which MTA1, a physiologic upstream regulator of Wnt1 and STAT3 gene chromatin, contributes to the development of neoplastic phenotypes in mammary epithelial cells and tumors. These findings offer a unique opportunity to study the first upstream common chromatin modifier of two pathways implicated in oncogenesis. Our working hypothesis is that "deregulation of MTA1 results in activation of the Wnt1, and STAT3 pathways, and consequently, confers neoplastic and metastatic properties to breast epithelial cells." To address these hypotheses, our Specific Aims are to: (1) Determine the mechanism of MTA1 regulation of Wnt1 expression, signaling, and functions in mammary epithelial cells; (2) Determine mechanism of MTA1-driven breast-to-lung metastasis; (3) Determine the expression characteristics and significance of MTA1 and its targets/effectors in human breast cancer. An innovative aspect of our proposal is the delineation of the mechanistic and functional significance of the MTA1- Wnt1, and the MTA1-STAT3 pathways in breast cancer cells. These studies will uniquely define the mechanisms of neoplastic and metastatic activities of MTA1. Our proposed research is significant, as the knowledge gained from this research will enhance our understanding of the critical regulatory pathways with established roles in breast cancer progression. In addition, this research will form the basis for new translational advances in identifying novel molecular targets, detecting, and treating breast cancer, by identifying MTA1 as a key master regulatory nodule. PUBLIC HEALTH RELEVANCE: This proposal is based on the original findings that MTA1 is a physiologic modifier of the Wnt1 and STAT3, two gene products implicated in oncogenesis and metastasis. The proposal is designed to establish the mechanism by which MTA1 contributes to the development of tumorigenic phenotypes in mammary epithelial cells and tumors.

描述（由申请人提供）：乳腺癌是女性新癌症病例的主要部位，是女性癌症死亡的第二大主要原因（仅次于肺癌）。然而，与乳腺癌相关的高死亡率是由于这些肿瘤散布的倾向，而原发性肿瘤则小且未被发现。 Wnt1和STAT3上游调节的基础分子机制，这是人类癌症中的两个主要转化分子，而这些癌症的进展和转移又不完全理解，但据信涉及主染色质修饰剂的扰动。例如，主染色质修饰剂的转移性肿瘤抗原1（MTA1）的过表达经常与人类乳腺癌的侵略性临床过程有关。尽管有关MTA1，WNT1和STAT3的信息显着增长，但有关MTA1的知识和含MTA1的含MTA1的核心调节复合物的直接靶标会调节乳腺上皮细胞的转化和转移仍然难以捉摸，并且是该应用的重点。 在这种情况下，我们最近的工作表明，乳腺上皮细胞中的MTA1放松管制在通过靶向特定基因染色质的靶向刺激Wnt1中起重要作用，即抑制Six3（Wnt1的直接核心压力）和STAT3染色质。此外，我们首次发现MTA1在转基因小鼠模型中是乳腺转移所必需的。该建议旨在建立一种机制，该机制MTA1是WNT1和STAT3基因染色质的生理上游调节剂，有助于乳腺上皮细胞和肿瘤中肿瘤表型的发展。这些发现提供了一个独特的机会，可以研究涉及肿瘤发生的两种途径的第一个上游常见染色质修饰符。我们的工作假设是：“ MTA1的放松管制导致WNT1和STAT3途径的激活，因此，将肿瘤和转移性特性赋予乳腺上皮细胞。”为了解决这些假设，我们的具体目的是：（1）确定MTA1调节Wnt1表达，信号传导和功能的机理； （2）确定MTA1驱动的乳腺转移的机制； （3）确定MTA1及其在人乳腺癌中的靶标/效应子的表达特征和重要性。 我们提案的一个创新方面是描述MTA1-WNT1的机械和功能意义，以及在乳腺癌细胞中的MTA1-STAT3途径。这些研究将唯一定义MTA1的肿瘤和转移活性的机制。我们提出的研究很重要，因为这项研究所获得的知识将增强我们对乳腺癌进展中既定作用的关键调节途径的理解。此外，这项研究将构成通过将MTA1识别为关键的主要调节结节，从而鉴定出新的分子靶标，检测和治疗乳腺癌的新转化进展的基础。 公共卫生相关性：该提案基于原始发现，即MTA1是Wnt1和STAT3的生理修饰符，这是涉及肿瘤发生和转移的两个基因产品。该提案旨在建立MTA1促进乳腺上皮细胞和肿瘤中肿瘤表型发展的机制。