MTA1 IN ONCOGENESIS

描述(申请人提供)：乳腺癌是女性新增癌症病例的主要部位，也是女性癌症死亡的第二大原因(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有扩散的倾向，而原发肿瘤很小，没有被发现。WNT1和STAT3是人类癌症中的两个主要转化分子，其上游调控以及这些癌症的进展和转移的分子机制目前尚不完全清楚，但据信涉及主要染色质修饰物的干扰。例如，转移性肿瘤抗原1(MTA1)是一种主要的染色质修饰物，其过度表达经常与人类乳腺癌的侵袭性临床过程有关。尽管关于MTA1、WNT1和STAT3的信息有了显著的增长，但关于MTA1和含有MTA1的共调节复合体的直接靶点调控乳腺上皮细胞转化和转移的机制的了解仍然是难以捉摸的，也是本应用的重点。 在这种背景下，我们最近的工作表明，乳腺上皮细胞中MTA1的去调控通过靶向特定基因染色质，即抑制Six3(WNT1的直接辅助抑制物)和STAT3染色质，在刺激WNT1中发挥重要作用。此外，我们首次发现，在转基因小鼠模型中，MTA1是乳房到肺转移所必需的。这一建议旨在建立MTA1，一个WNT1和STAT3基因染色质的生理性上游调节因子，通过其促进乳腺上皮细胞和肿瘤的肿瘤表型发展的机制。这些发现为研究与肿瘤发生有关的两个途径的第一个上游共同染色质修饰物提供了一个独特的机会。我们的工作假设是“解除MTA1的调控会导致WNT1和STAT3通路的激活，从而赋予乳腺上皮细胞肿瘤和转移的特性。”针对这些假说，我们的具体目标是：(1)确定MTA1对乳腺上皮细胞WNT1表达、信号转导和功能的调控机制；(2)确定MTA1驱动的乳腺向肺转移的机制；(3)确定MTA1及其靶/效应物在人类乳腺癌中的表达特点和意义。 我们提案的一个创新方面是描述了MTA1-WNT1和MTA1-STAT3通路在乳腺癌细胞中的机制和功能意义。这些研究将独特地确定MTA1的肿瘤和转移活性的机制。我们建议的研究具有重要意义，因为从这项研究中获得的知识将增强我们对乳腺癌进展中已确立的作用的关键调控途径的理解。此外，这项研究将通过将MTA1识别为关键的主调节结节，为在识别新的分子靶点、检测和治疗乳腺癌方面取得新的翻译进展奠定基础。 公共卫生相关性：这项建议是基于最初的发现，即MTA1是WNT1和STAT3的生理修饰物，这两个基因产物与肿瘤的发生和转移有关。该提案旨在建立MTA1促进乳腺上皮细胞和肿瘤致瘤表型发展的机制。

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.