Dissecting Tumor Heterogeneity by Analyzing Signaling Pathway Requirements.

通过分析信号通路要求来剖析肿瘤异质性。

• 批准号: 8678872
• 负责人: Eran Robert Andrechek
• 金额: $ 29.82万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678872
• 关键词: Ablation; Address; Affect; Bioinformatics; Biological Markers; Biological Models; Breast Cancer Cell; Cancer Patient; Cancer cell line; Cell Cycle; Cell Line; Clinical; Clinical Treatment; Data; Detection; Development; Diagnosis; E2F transcription factors; E2F1 gene; ERBB2 gene; Future; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genetic Crosses; Genetic screening method; Goals; Growth; Heterogeneity; Histology; Human; In Vitro; Individual; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Metastatic to; Methods; Mission; Modeling; Molecular; Mouse Mammary Tumor Virus; Mus; Mutation; Neoplasm Metastasis; Pathway interactions; Patients; Pattern; Play; Prevalence; Process; Public Health; Regulation; Research; Risk Assessment; Roche brand of trastuzumab; Role; Sampling; Signal Pathway; Signaling Pathway Gene; Stratification; Testing; Therapeutic Human Experimentation; Thinking; Transgenic Mice; Transgenic Model; Transgenic Organisms; Translating; United States National Institutes of Health; Work; base; expectation; high risk; human disease; in vivo; innovation; insight; malignant breast neoplasm; mouse model; novel; outcome forecast; overexpression; trait; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Amplification and overexpression of HER2 (Neu, ErbB2) is noted in 20-30% of breast cancers. Despite development of targeted therapies such as Herceptin, treatment fails in an alarmingly high proportion of cases, likely due to activation o additional signaling pathways that circumvent treatment. Understanding the role of pathways, such as the E2F transcription factors, in this process will be critical for refining treatment for HER2+ breast cancer. The long term goal of our work is to elucidate the mechanism and progression of breast cancer through molecular and bioinformatic means, with a particular focus on the E2Fs. The immediate objective of this project is to establish the role of the E2Fs in a mouse model of HER2+ breast cancer, determine the mechanism of action and examine how these pathways are utilized in human breast cancer. The central hypothesis of this proposal is that the E2F transcription factors mediate HER2+ breast cancer. Our hypothesis has been predicated on results from a mouse model system and from preliminary results using gene expression from human breast cancer. Specifically, bioinformatic predictions demonstrated differential roles for the E2Fs both in the MMTV-Neu mouse model of HER2+ breast cancer and in human HER2+ tumor samples. Initial results from interbreeding MMTV-Neu mice with E2F knockouts also support this hypothesis. The rationale for the proposed research is that, once it is known how E2Fs regulate HER2+ breast cancer, the downstream targets can be therapeutically targeted, resulting in new and innovative approaches to treatment. We plan to test our central hypothesis and accomplish the objective of this application by investigating the following three specific aims. In the first aim we will test the hypothesis that the E2Fs regulate HER2+ breast cancer in mouse model systems through genetic crosses where we ablate individual E2Fs in the MMTV-Neu transgenic model systems. In the second aim we will elucidate the genetic mechanisms by which E2Fs regulate alterations to tumor latency, growth rate, histology and metastasis through gene expression studies, confirmed through in vitro and in vivo tests. The objective of this aim is to define the genetic mechanisms by which specific E2Fs affect tumorigenesis and to validate these genetic pathways. In the final aim we will assess the role of E2F transcription factors in HER2+ human breast cancer. This proposal is innovative because it will elucidate a novel role for E2F transcription factors in HER2+ breast cancer. This will offer a novel interpretation of the role of E2Fs, as opposed to traditional thinking that places E2Fs simply as cell cycle regulators. This contribution is significant because it will establish a role for the E2Fs in HER2+ breast cancer. Clearly this project will define the role, mechanism and human impact of the E2Fs in HER2+ breast cancer. Once the role for E2Fs in tumor development and progression is determined, the E2Fs will be explored as a clinical biomarker in future work. The implications of uncovering a role for E2Fs in regulation of HER2+ breast cancer are profound, with the potential for development of clinical therapies to enhance survival.

描述（由申请人提供）：在20-30％的乳腺癌中发现了HER2（NEU，ERBB2）的扩增和过表达。尽管开发了诸如赫赛汀等有针对性的疗法，但治疗的比例令人震惊，可能是由于激活o绕过治疗的其他信号传导途径。了解途径（例如E2F转录因子）在此过程中的作用对于精炼HER2+乳腺癌的治疗至关重要。我们工作的长期目标是通过分子和生物信息学手段阐明乳腺癌的机制和进展，特别关注E2F。该项目的直接目的是确定E2F在HER2+乳腺癌的小鼠模型中的作用，确定作用机理，并检查如何在人类乳腺癌中使用这些途径。该提议的中心假设是E2F转录因子介导HER2+乳腺癌。我们的假设是基于小鼠模型系统的结果以及使用人类乳腺癌的基因表达的初步结果的结果。具体而言，生物信息学预测表明，在HER2+乳腺癌的MMTV-NEU小鼠模型和人类HER2+肿瘤样品中，E2F的差异作用。杂交MMTV-NEU小鼠与E2F敲除的初始结果也支持这一假设。拟议研究的理由是，一旦知道E2F如何调节HER2+乳腺癌，就可以将下游靶标的靶向靶向，从而导致新的和创新的治疗方法。我们计划通过研究以下三个特定目标来检验我们的中心假设并实现该应用的目标。在第一个目的中，我们将测试以下假设：E2FS通过遗传杂交调节小鼠模型系统中的HER2+乳腺癌，在该杂交中，我们在MMTV-NEU转基因模型系统中消融单个E2F。在第二个目的中，我们将通过体外和体内检测证实，通过基因表达研究来调节肿瘤潜伏期，生长速率，组织学和转移的改变的遗传机制。该目的的目的是定义特定E2F影响肿瘤发生并验证这些遗传途径的遗传机制。在最终目标中，我们将评估E2F转录因子在HER2+人乳腺癌中的作用。该建议具有创新性，因为它将阐明E2F转录因子在HER2+乳腺癌中的新作用。这将提供对E2FS作用的新颖解释，而不是将E2F作为细胞周期调节剂的传统思想。这项贡献很重要，因为 它将在HER2+乳腺癌中确立E2F的作用。显然，该项目将定义E2F在HER2+乳腺癌中的作用，机制和人类影响。一旦确定了E2F在肿瘤发育和进展中的作用，将在未来工作中探索E2Fs作为临床生物标志物。发现E2F在调节HER2+乳腺癌调节中的作用的含义是深远的，具有开发临床疗法以提高生存率的潜力。