MiR-199~214 cluster at the crossroads of plasticity and malignancy in breastcancer

MiR-199~214簇处于乳腺癌可塑性和恶性的十字路口

基本信息

批准号：
10055955
负责人：
Antoine Elias Karnoub
金额：
$ 39.57万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055955
关键词：
Biological Biological Markers Blood Blood specimen Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer therapy Breast Carcinoma Breast Oncology Breast cancer metastasis Cancer Biology Cancer Etiology Cell Nucleus Cells Clinic Clinical Connective Tissue Data Depressed mood Development Diagnosis Diagnostic Disease Disseminated Malignant Neoplasm Distant Down-Regulation ERBB2 gene Exhibits FOXP2 gene Generations Genetic Transcription Genomic approach In Vitro Inflammation Investigation Language Development Lead Ligands Light Link Maintenance Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Membrane Mesenchymal Stem Cells Metastatic breast cancer MicroRNAs Molecular Molecular Analysis Natural regeneration Neoplasm Metastasis Pathogenesis Pathway interactions Patients Phenocopy Phenotype Plant Roots Pre-Clinical Model Process Prognosis Prognostic Marker Property RNA Recurrence Relapse Repression Resistance Role Signal Pathway Signal Transduction Specimen Speech Development Therapeutic Intervention Time Tissues Xenograft procedure base breast cancer progression breast malignancies cancer cell cancer stem cell cell motility cohort effective therapy experimental study forkhead protein in vivo innovation insight knock-down malignant breast neoplasm mouse model neoplastic cell new growth novel pre-clinical receptor self-renewal stem cell division stem cells stem-like cell stromal progenitor targeted treatment therapeutic target therapy development tool trait tumor tumor initiation tumor microenvironment tumor progression wound

项目摘要

Malignant progression of cancer is associated with increased resistance of neoplastic cells to existing therapies, and is responsible for the majority of the >40,000 breast-cancer-related yearly fatalities in the US alone. A better understanding of the malignant features of breast cancer cells (BCCs) and how they become metastatic will lead to the development of more effective therapies that save patients' lives. Our prior studies have identified that the microenvironment of breast tumors is enriched for certain progenitor cells called mesenchymal stem cells (MSCs), cells that otherwise contribute to the maintenance and regeneration of connective tissues during wounding and inflammation. Importantly, we demonstrated that tumor-associated MSCs exerted potent pro-malignant functions, causing even poorly metastatic breast cancer cells (BCCs) to spread to distant tissues. These findings ascribed a novel role for MSCs as important determinants of breast cancer pathogenesis and provided new insights into cancer metastasis. To elucidate the heterotypic interactions that MSCs establish with BCCs in the context of metastasis, we conducted detailed molecular analyses of MSC-stimulated BCCs, and identified miR-199a~214 as the most MSC-stimulated microRNA in BCCs. We present evidence that miR-199a~214 promotes cancer stem cell (CSC) -like properties in cancer cells, and that its actions involve the downregulation of FOXP2, a forkhead transcription factor tightly associated with speech and language development. We show that FOXP2 knockdown in BCCs phenocopies miR-199a~214 expression, and that it is sufficient in promoting CSC propagation, tumor-initiation, and metastasis. Importantly, we show that elevated miR-199a and depressed FOXP2 expression levels represent prominent features of malignant clinical breast cancer, associating significantly with triple-negative (TN) and HER2-enriched breast cancers. In this proposal, we will elucidate the involvement of the newly discovered miR-199a-FOXP2 axis in breast cancer pathogenesis. Using in vitro, in vivo, and clinical approaches, we will: (1) determine the role of miR- 199a as a biomarker of advanced clinical disease, and demonstrate its essentiality for metastasis in pre-clinical models so as to establish its relevance as a target in breast cancer therapy; (2) elucidate the metastasis- associated activities of miR-199a~214 in vitro and in vivo; and (3) decipher the regulatory molecular networks underlying the induction of miR-199a in BCCs, elucidate how such networks converge on and regulate FOXP2 silencing, and determine how FOXP2 exerts its downstream functions. Collectively, our proposed studies will identify and define novel and important molecular determinants that regulate breast CSC genesis, maintenance, and metastasis. These insights would shed light on the inner workings of breast cancer's most malignant cells, and will serve to provide novel tools of potential utility in the prognosis and therapy of malignant disease.

癌症的恶性进展与肿瘤细胞对现有物质的抵抗力增加有关。美国每年有超过 40,000 例乳腺癌相关死亡，其中大部分是由该病造成的独自的。更好地了解乳腺癌细胞 (BCC) 的恶性特征及其演变过程转移将导致更有效的疗法的开发来挽救患者的生命。我们之前的研究已经发现，乳腺肿瘤的微环境在某些方面是丰富的称为间充质干细胞 (MSC) 的祖细胞，这些细胞有助于维持和受伤和炎症期间结缔组织的再生。重要的是，我们证明了肿瘤相关间充质干细胞发挥强大的促癌功能，甚至导致转移性较差的乳腺癌细胞（BCC）扩散到远处组织。这些发现赋予 MSC 重要的新作用乳腺癌发病机制的决定因素，并为癌症转移提供了新的见解。为了阐明转移背景下 MSC 与 BCC 建立的异型相互作用，我们对 MSC 刺激的 BCC 进行了详细的分子分析，并确定 miR-199a~214 是最重要的 BCC 中 MSC 刺激的 microRNA。我们提供了 miR-199a~214 促进癌症干细胞的证据癌细胞中具有类似 (CSC) 的特性，其作用涉及叉头 FOXP2 的下调转录因子与言语和语言发展密切相关。我们证明 FOXP2 BCC 中的敲低可复制 miR-199a~214 的表达，并且足以促进 CSC 增殖、肿瘤起始和转移。重要的是，我们发现 miR-199a 升高且 miR-199a 降低 FOXP2 表达水平代表了恶性临床乳腺癌的显着特征，对三阴性（TN）和富含 HER2 的乳腺癌有显着影响。在本提案中，我们将阐明新发现的 miR-199a-FOXP2 轴在乳腺中的参与癌症发病机制。使用体外、体内和临床方法，我们将：（1）确定 miR- 199a作为晚期临床疾病的生物标志物，并在临床前证明其对于转移的重要性模型以确定其作为乳腺癌治疗靶标的相关性； (2) 阐明转移- miR-199a~214的体外和体内相关活性； (3) 破译调控分子网络在 BCC 中诱导 miR-199a 的基础上，阐明此类网络如何汇聚并调节 FOXP2 沉默，并确定 FOXP2 如何发挥其下游功能。总的来说，我们提出的研究将识别和定义新颖且重要的分子决定因素调节乳腺 CSC 的发生、维持和转移。这些见解将揭示内在乳腺癌最恶性细胞的工作原理，并将有助于提供具有潜在用途的新工具恶性疾病的预后和治疗。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long noncoding RNA-mediated activation of PROTOR1/PRR5-AKT signaling shunt downstream of PI3K in triple-negative breast cancer.

在三阴性乳腺癌中，长非编码 RNA 介导的 PROTOR1/PRR5-AKT 信号传导分流至 PI3K 下游。

DOI：
发表时间：
2022-10-25
期刊：
影响因子：
11.1
作者：
Tu, Zhenbo;Hu, Yi;Raizada, Devesh;Bassal, Mahmoud A;Tenen, Daniel G;Karnoub, Antoine E
通讯作者：
Karnoub, Antoine E

The LINC01119-SOCS5 axis as a critical theranostic in triple-negative breast cancer.

LINC01119-SOCS5 轴作为三阴性乳腺癌的关键治疗诊断。

DOI：
发表时间：
2021-05-31
期刊：
影响因子：
5.9
作者：
Tu, Zhenbo;Schmoellerl, Johannes;Mariani, Odette;Zheng, Yurong;Hu, Yi;Vincent;Karnoub, Antoine E
通讯作者：
Karnoub, Antoine E

In vivo library screening identifies the metabolic enzyme aldolase A as a promoter of metastatic lung colonization.

体内文库筛选将代谢酶醛缩酶 A 鉴定为转移性肺定植的促进剂。

DOI：
发表时间：
2021-05-21
期刊：
影响因子：
5.8
作者：
Tu, Zhenbo;Hou, Shengqi;Zheng, Yurong;Abuduli, Maerjianghan;Onder, Tamer;Intlekofer, Andrew M;Karnoub, Antoine E
通讯作者：
Karnoub, Antoine E

Targeting Cancer Stem Cells-A Renewed Therapeutic Paradigm.

靶向癌症干细胞——新的治疗范式。