MTA1 in Oncogenesis

描述(申请人提供)：包括乳腺癌在内的许多人类癌症的高死亡率是由于这些肿瘤有扩散的倾向，而原发肿瘤很小且未被发现。转移肿瘤抗原1(MTA1)是影响肿瘤转移的分子之一。过去的十年见证了癌细胞中MTA家族生物学上最令人兴奋的时期之一。例如，我们和其他人已经确定，主要染色质修饰物MTA1的过度表达经常与人类乳腺癌的侵袭性临床病程有关，并且它的过度表达会导致转基因小鼠的增殖和肿瘤形成。尽管MTA1家族的创始成员MTA1在NuRD复合体中的重要性很高，在人类癌症中广泛表达，但目前尚不清楚MTA1或其直接靶点是否参与DNA损伤反应途径，从而影响癌细胞对放射治疗的反应性--放射治疗是目前用于癌症治疗的主要治疗方案。在此背景下，最近，我们试图评估MTA1在癌细胞DNA损伤反应中的意义。如下所述，我们的初步研究发现，MTA1是有效的DNA损伤反应的关键修饰物，因为它的耗尽使细胞对电离辐射(IR)诱导的DNA损伤高度敏感，并且MTA1可以部分修复DNA修复P53缺失细胞中的缺陷。我们对这些发现的解读是，MTA1在有效的DNA损伤反应和调节癌细胞的辐射敏感性方面发挥着固有的作用。这些发现为研究MTA1和/或其直接靶点在DNA损伤反应中的机制提供了一个独特的机会。这一修订将检验工作假说，即“MTA1和/或MTA1-靶通过p53依赖和非依赖的方式对DNA损伤反应作出贡献。”调节MTA1对DNA损伤反应的调节可能会对癌细胞的敏感性和耐药性产生重大影响。这一修订建议代表了PI对界定MTA1或其效应物在人类癌症生物学特别是乳腺癌生物学中的意义的长期承诺。在这里，我们建议研究MTA1通路作为一个新的参与者在不断增长的DNA损伤反应机制网络中的作用。这一修订申请将在所要求的24个月资金内大力追求以下三个重点、可实现的具体目标：(1)MTA1在DNA损伤反应中的作用和意义以及MTA1调节p53水平的机制基础；(2)MTA1在DNA损伤反应中上调p21Waf1的分子基础和意义；(3)在生理相关模型系统中，MTA1作为乳腺癌细胞对DSB诱导治疗敏感性的上游决定因素的作用。我们修订的一个创新方面是关注在癌细胞中具有既定作用的分子，并使用与生理相关的模型。PI和他的顾问/合作者认为，从这个项目中获得的知识将成为新的机械进展的基础，并确定新的途径，将NuRD复合体及其目标与DNA损伤反应连接起来。我们的研究意义重大，因为这项修订研究将填补知识空白，将增强我们对新的关键调控途径的理解，该途径在癌症进展中具有既定的作用。这项工作将增强我们设计策略的能力，以改善MTA1升高的乳腺癌患者的IR治疗效果。由于这里研究的分子和放射治疗不是癌症特异性的，从当前研究中吸取的经验教训将对MTA1升高的其他癌症产生重大影响。 公共卫生相关性：我们的研究意义重大，因为这项修订研究要填补的知识空白将增强我们对新的关键调控途径的理解，该途径在癌症进展中具有既定的作用。此外，这也将增强我们设计策略的能力，以提高MTA1升高的乳腺癌患者的放射治疗疗效。由于这里研究的分子和放射治疗不是癌症特有的，从当前研究中吸取的经验教训将对MTA1升高的其他癌症产生重大影响。

DESCRIPTION (provided by applicant): The high mortality rate associated with many of human cancers, including breast is due to a propensity for these tumors to spread while the primary tumors are small and undetected. One of the molecules that have been shown to influence metastasis is metastatic tumor antigen 1 (MTA1). The last decade has witnessed one of the most exciting periods in the biology of MTAs family in cancer cells. For example, we and others have established that overexpression of MTA1, a master chromatin modifier, is frequently associated with an aggressive clinical course in human breast cancer and its overexpression leads to hyperplasia and tumor formation in transgenic mice. Despite the high significance of MTA1, the founding family member, in the NuRD complex and its wide spread upregulation in the human cancer, it remains unknown whether MTA1 or its direct targets participate in the DNA damage response pathway and thus, could influence the responsiveness of cancer cells to radiation therapy - a major treatment regimen currently used for cancer treatment. In this context, recently, we attempted to assess the significance of MTA1 in DNA damage response in cancer cells. As described below, our preliminary studies have discovered that MTA1 is a critical modifier for efficient DNA damage response as its depletion hypersensitizes cells to ionizing radiation (IR)-induced DNA damage, and that MTA1 can partially restore a defect in DNA repair p53-null cells. We interpret these findings as suggesting that MTA1 plays an inherent role in efficient DNA damage responsiveness and modulation of cancer cell's radio-sensitivity. These findings offer a unique opportunity to study the mechanistic involvement of MTA1 and/or its direct targets in DNA damage response. This revision will test the working hypothesis is that "MTA1 and/or MTA1-targets contribute to DNA damage response via both p53-dependent and -independent manner." Regulation of MTA1 regulation of DNA damage response is likely to have significant consequences relating to the sensitivity versus resistance of cancer cells. This revision proposal represents a long-term commitment of the PI to define the significance of MTA1 or its effectors in the biology of human cancer and breast cancer in-particular. Here we propose to investigate the role of the MTA1 pathway as a new player to the growing network of DNA damage response mechanisms. This revision application will vigorously pursue the following three focused, achievable Specific Aims within the requested 24-months of funding: (1) The role and significance of MTA1 in DNA damage response and mechanistic basis of MTA1 regulation of p53 levels; (2) The molecular basis and significance of MTA1 upregulation of p21Waf1 in DNA damage response; (3) The role of MTA1 as an upstream determinant of sensitivity of breast cancer cells to DSB inducing therapy in physiologic relevant model systems. An innovative aspect of our revision is the focus on a molecule with an established role in cancer cells and use of physiologic relevant models. The PI and his consultants/collaborators believe that the knowledge gained from this project will form the basis for new mechanistic advances and identify novel pathways, connecting NuRD complexes and its targets with the DNA damage response. Our research is significant in that the knowledge-gap to be filled by this revision research will enhance our understanding of a new critical regulatory pathway with established roles in cancer progression. This work will enhance our ability to design strategies to improve the efficacy of IR therapy for breast cancer patients with high MTA1. As molecule studied here and radiotherapy is not cancer specific, lessons learned from the current study will have a significant impact on other cancers with increased MTA1. PUBLIC HEALTH RELEVANCE: Our research is significant in that the knowledge-gap to be filled by this revision research will enhance our understanding of a new critical regulatory pathway with established roles in cancer progression. In addition, this also will enhance our ability to design strategies to improve the efficacy of radiation therapy for breast cancer patients with high MTA1. As molecule studied here and radiotherapy are not cancer specific, lessons learned from the current study will have a significant impact on other cancers with increased MTA1.