MTA1 IN ONCOGENESIS

描述（由申请人提供）：乳腺癌是女性新发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倾向于扩散，而原发肿瘤很小且未被发现。Wnt 1和STAT 3是人类癌症中的两种主要转化分子，其上游调控的分子机制以及这些癌症的进展和转移目前还不完全清楚，但据信涉及主染色质修饰剂的扰动。例如，转移性肿瘤抗原1（MTA 1）（一种主染色质修饰剂）的过表达通常与人乳腺癌的侵袭性临床过程相关。尽管关于MTA 1、Wnt 1和STAT 3的信息显著增长，但关于MTA 1和含有MTA 1的共调节复合物的直接靶点调节乳腺上皮细胞转化和转移的机制的知识仍然难以捉摸，并且是本申请的焦点。 在这种情况下，我们最近的工作表明，在乳腺上皮细胞中的MTA 1失调发挥了重要作用，刺激Wnt 1通过靶向特定的基因染色质，即抑制Six 3（Wnt 1的直接辅阻遏物），和STAT 3染色质。此外，我们首次在转基因小鼠模型中发现，MTA 1是乳腺至肺转移所必需的。该提案旨在建立MTA 1（Wnt 1和STAT 3基因染色质的生理上游调节因子）促进乳腺上皮细胞和肿瘤中肿瘤表型发展的机制。这些发现提供了一个独特的机会，研究第一个上游共同染色质修饰的两个途径参与肿瘤发生。我们的工作假设是，“MTA 1的失调导致Wnt 1和STAT 3通路的激活，从而赋予乳腺上皮细胞肿瘤和转移特性。“为了解决这些假设，我们的具体目标是：（1）确定MTA 1调节乳腺上皮细胞中Wnt 1表达，信号传导和功能的机制;（2）确定MTA 1驱动的乳腺至肺转移的机制;（3）确定MTA 1及其靶点/效应物在人类乳腺癌中的表达特征和意义。 我们的提案的一个创新方面是描绘了乳腺癌细胞中MTA 1-Wnt 1和MTA 1-STAT 3通路的机制和功能意义。这些研究将独特地定义MTA 1的肿瘤和转移活性的机制。我们提出的研究是重要的，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具有既定作用的关键调控途径的理解。此外，这项研究将形成新的翻译进展的基础，在确定新的分子靶点，检测和治疗乳腺癌，通过确定MTA 1作为一个关键的主调节结节。 公共卫生相关性：该建议基于最初的发现，即MTA 1是Wnt 1和STAT 3的生理修饰剂，这两种基因产物与肿瘤发生和转移有关。该提案旨在建立MTA 1促进乳腺上皮细胞和肿瘤中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.