Roles of miR29c-ID2 axis in tumor initiating cells of breast ductal carcinoma in situ

miR29c-ID2轴在乳腺导管原位癌肿瘤起始细胞中的作用

• 批准号: 9280611
• 负责人: Yin Liu
• 金额: $ 4.4万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280611
• 关键词: Animal Model; Biological Assay; Breast Cancer Prevention; Cancer Biology; Cell Cycle Progression; Cells; Clinical; Comprehensive Cancer Center of Wake Forest University; Computer Retrieval of Information on Scientific Projects Database; Disease; Ductal Epithelial Cell; E protein; Enzymes; Fatty-acid synthase; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Grant; Grapes; Growth; ID2 gene; In Situ; Incidence; Journals; Knock-out; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Manuscripts; Mentors; Molecular; Noninfiltrating Intraductal Carcinoma; Normal Cell; Oncogenic; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Premalignant Cell; Prevention; Preventive measure; Process; RNA Interference; Recurrence; Reporter; Research; Research Personnel; Research Training; Resveratrol; Role; Sampling; Seasons; Series; Stem cells; System; Techniques; Technology; Testing; Tetanus Helper Peptide; Therapeutic; Time; Training; Training Programs; Transgenic Animals; Translational Research; Tumor Initiators; Work; Writing; Xenograft Model; base; cancer cell; clinical practice; design; experimental study; in vivo; knock-down; lipid metabolism; malignant breast neoplasm; meetings; mouse model; notch protein; novel; novel therapeutics; prevent; promoter; protein E; public health relevance; self-renewal; skills; small molecule; three-dimensional modeling; transcription factor; tumor; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Ductal carcinoma in situ (DCIS) is an early-stage form of breast cancer that accounts for over 20% of all breast cancers in the US. This proposal aims to elucidate the underlying molecular and pathological mechanisms of DCIS. Our recent work revealed that the expression of miR29c in tumor-initiating cells was significantly down- regulated in DCIS compared to normal cells. Furthermore, miR29c suppressed expression of the ID2 gene, a dedifferentiation factor, in both non-tumorigenic and premalignant cells. We also found that ID2 contributed to formation of tumor-initiating cells in DCIS. As a transcription regulator, ID2 controls gene expression by sequestering bHLH transcription factors; we found that ID2 up-regulated expression of both the SOX2 and fatty acid synthase (FASN) genes. SOX2 is a well- known self-renewal regulator of stem cells, while FASN is a key enzyme for lipid metabolism and plays a critical role in tumor progression. We also found that the FASN gene is significantly up-regulated in tumor-initiating cells of DCIS and that resveratrol, a compound found abundantly in grapes, suppressed FASN expression and blocked growth of DCIS. Among resveratrol derivatives, the small-molecule drug pterostilbene was ten times more effective than others in suppressing FASN. Based on these novel discoveries, we hypothesize that (a) DCIS is initiated from tumor-initiating cells in a process controlled by the miR29c-ID2 axis, (b) ID2 promotes self-renewal of tumor-initiating cells by regulating SOX2 and FASN through sequestration of bHLH transcription factors; and (c) pterostilbene prevents DCIS formation by suppressing FASN expression. To test these hypotheses, we propose a series of experiments to: determine the mechanisms of the molecular pathway and validate in clinical samples (Aim 1); clarify the role of miR29c and ID2 in DCIS initiation in various animal models (Aim 2); and then test the potential therapeutic utility of selected small molecule compounds in DCIS prevention (Aim 3). The long-term objective of this proposed research is to develop a novel therapeutic strategy for DCIS prevention, which will have a significant impact on current clinical practice. Training will be provided to the applicant through relevant course work, weekly seminars and journal club presentations, one-to-one meetings with the primary mentor, and critical analysis and discussions of the applicant's progress with the mentor team. In addition, the research training program is designed to enable (i) generation of conceptual frameworks, (ii) exploration of cutting-edge technology to execute the planned project, (iii) enhancement of grant- and manuscript-writing skills, and (iv) building a network with top-notch cancer researchers through scientific meetings. Both the state-of-art facilities available at the Comprehensive Cancer Center of Wake Forest University and the seasoned mentor will facilitate the applicant's progress toward becoming an independent investigator who conducts clinically meaningful translational research in cancer biology.

 描述（由适用提供）：导管癌（DCIS）是一种早期乳腺癌形式，占美国所有乳腺癌的20％以上。该建议旨在阐明DCI的基本分子和病理机制。我们最近的工作表明，与正常细胞相比，DCI中MIR29C在肿瘤发射细胞中的表达显着下调。此外，miR29c抑制了非肿瘤和前启示性细胞中ID2基因的表达，这是一种去分化因子。我们还发现，ID2有助于DCIS中肿瘤发射细胞的形成。作为转录调节剂，ID2通过隔离BHLH转录因子来控制基因表达。我们发现ID2上调了SOX2和脂肪酸合酶（FASN）基因的表达。 SOX2是众所周知的自我更新调节剂，而FASN是脂质代谢的关键酶，并且在肿瘤进展中起着至关重要的作用。我们还发现，FASN基因在DCIS的肿瘤发射细胞中显着上调，并且白藜芦醇是在图中发现的绝对化合物，抑制了FASN表达并阻塞了DCIS的生长。在白藜芦醇衍生物中，小分子药物pterostilbene在抑制FASN方面的有效性高十倍。基于这些新发现的发现，我们假设（a）DCI是在由MiR29C-ID2轴控制的过程中从肿瘤引起的细胞中引发的，（b）ID2通过通过BHLH转录因子的训练来促进SOX2和FASN的反思和FASN来促进肿瘤启动细胞的自我更新； （c）pterostilbene通过抑制FASN表达来防止DCIS形成。为了检验这些假设，我们提出了一系列实验以：确定分子途径的机理并在临床样本中验证（AIM 1）；阐明MiR29C和ID2在DCIS倡议中在各种动物模型中的作用（AIM 2）；然后测试DCIS预防中选定的小分子化合物的潜在理论效用（AIM 3）。这项拟议的研究的长期目标是为预防DCIS制定一种新型的治疗策略，这将对当前的临床实践产生重大影响。培训将通过相关课程工作，每周的准则和期刊俱乐部演讲，与主要导师一对一的会议以及对申请人与心理团队的进步进行批判性分析以及讨论的培训。此外，研究培训计划旨在使（i）生成概念框架，（ii）探索前沿技术以执行计划的项目，（iii）通过科学会议通过科学会议来增强授予和手稿编写技能，以及（iv）与顶级癌症研究人员建立网络。维克森林大学综合癌症中心和经验丰富的导师综合癌症中心可用的最先进的设施都将促进申请人成为一名独立研究者的进步，该研究人员在癌症生物学领域进行了临床意义的转化研究。