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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细胞的抵抗力增加有关

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.

DOI：
10.1073/pnas.2203180119
发表时间：
2022-10-25
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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.

In vivo gain-of-function cDNA library screening for colonization genes in a mouse model of pulmonary metastasis.