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（由申请人提供）：导管原位癌 (DCIS) 是乳腺癌的一种早期形式，占美国所有乳腺癌的 20% 以上。本提案旨在阐明 DCIS 的潜在分子和病理机制。我们最近的工作表明，与正常细胞相比，DCIS 中肿瘤起始细胞中 miR29c 的表达显着下调。此外，miR29c 抑制了 ID2 基因的表达。我们还发现 ID2 有助于 DCIS 中肿瘤起始细胞的形成，作为转录调节因子，ID2 通过隔离 bHLH 转录因子来控制基因表达。 SOX2 和脂肪酸合酶 (FASN) 基因的表达受调节 SOX2 是众所周知的干细胞自我更新调节因子，而 FASN 是脂质代谢的关键酶，在脂质代谢中发挥着关键作用。我们还发现，FASN 基因在 DCIS 肿瘤起始细胞中显着上调，而白藜芦醇（一种在葡萄中大量存在的化合物）可抑制 FASN 表达并阻止 DCIS 的生长。 -分子药物紫檀芪在抑制 FASN 方面的效果比其他药物高十倍。基于这些新发现，我们认为 (a) DCIS 是从肿瘤起始开始的。 (b) ID2 通过隔离 bHLH 转录因子来调节 SOX2 和 FASN，从而促进肿瘤起始细胞的自我更新；(c) 紫檀芪通过抑制 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来：确定分子途径的机制并在临床样本中进行验证（目标 1）； miR29c 和 ID2 在各种动物模型中的 DCIS 起始中的作用（目标 2）；然后测试选定的小分子化合物在预防 DCIS 中的潜在治疗效用（目标 3）。 DCIS 预防策略，这将对当前的临床实践产生重大影响，将通过相关课程、每周研讨会和期刊俱乐部演讲、与主要导师的一对一会议以及批判性分析和分析向申请人提供培训。的讨论此外，研究培训计划的目的是（i）生成概念框架，（ii）探索尖端技术来执行计划的项目，（iii）增强资助和手稿。 - 写作技巧，以及 (iv) 通过科学会议与顶尖癌症研究人员建立网络 维克森林大学综合癌症中心提供的最先进的设施和经验丰富的人员将促进申请人成为导师。进行临床研究的独立研究者癌症生物学领域有意义的转化研究。