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Identifying a network of microRNAs and genes that regulate breast tumor metastasi

识别调节乳腺肿瘤转移的 microRNA 和基因网络

基本信息

批准号：
8773677
负责人：
Huiping Liu
金额：
$ 24.15万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8773677
关键词：
Algorithms BRCA1 gene Biological Assay Biological Markers Biomedical Engineering Blood Circulation Breast Breast Cancer Cell Breast Cancer Model Bypass Cancer Patient Cancer cell line Cause of Death Cell physiology Cells Chemistry Chicago Chromatin Clinical Clinical Medicine Correlation Studies Data Detection Drug Compounding Drug resistance EZH2 gene Electrophoretic Mobility Shift Assay Epithelial Family Fatty acid glycerol esters Future Gene Targeting Genes Genetic Goals Human In Vitro Knowledge Length Lentivirus Vector Luciferases Lung Malignant Neoplasms Mammary Neoplasms Mammary gland Medicine Mentors Mesenchymal Messenger RNA MicroRNAs Microarray Analysis Modeling Molecular Monitor Mus Mutation Neoplasm Metastasis Nucleotides Optical reporter Patients Phase Property Protocols documentation Regulation Reporting Research Personnel Research Training Resistance Small RNA Specimen Stem cells Technology Therapeutic Toxic effect Transcriptional Regulation Translating Transplantation Tumor-Derived United States Universities Western Blotting Xenograft Model abstracting base bioluminescence imaging breast cancer diagnosis cancer cell cancer initiation cancer therapy clinical application improved in vivo innovation lymph nodes malignant breast neoplasm mortality neoplastic cell non-invasive imaging novel overexpression post-doctoral training pre-clinical preclinical study prevent promoter therapeutic target transcription factor tumor tumor growth tumor initiation tumor progression

项目摘要

Proposal: Identifying a network of miRNAs and genes that regulate breast tumor metastasis Abstract Metastasis is the major cause of death in breast cancer patients. However, the molecular mechanisms underlying tumor initiation and metastasis are not clear. We have recently identified tumor initiation cells (TICs) from human breast tumors 1,2. TICs carry certain properties of stem cells, are more resistant to conventional cancer therapies, and are involved in tumor metastasis. How to effectively target TICs or metastasis initiating cells (MICs) thus becomes one of the most propelling questions. Endogenous single strand small RNAs of 20- 22 nucleotides in length, known as microRNAs (miRNAs, miRs), have emerged to be powerful regulators of tumor progression 3-15. In this project, we aim to characterize novel miRs that regulate human breast cancer initiation and metastasis and identify their target genes. Then in our future endeavors, we will examine miR regulation mechanisms at the transcriptional level and further translate our understanding to clinical applications, such as novel cancer biomarkers or therapeutics. Most previous metastasis models are limited in their ability to fully represent human tumors, due to genetic changes accumulated in culture for human cancer cell lines, genetic differences in mouse tumor models compared to human tumors, and bypassing the natural steps of metastasis via bloodstream inoculations. This project will take advantage of our recently established human-in-mouse breast cancer models, which are derived from clinical tumor specimens and develop spontaneous lung or lymph node metastases upon orthotopic transplantation into mouse mammary fat pads. To closely monitor breast tumor initiation and metastasis in vivo, we have also transduced primary cancer cells with optical reporters and improved the detection sensitivity to 10 cells in vivo via non-invasive bioluminescence imaging. MiRs are more stable and resistant to analysis protocols than mRNAs, thus serving as promising novel cancer biomarkers. Furthermore, they are endogenous small RNAs with little toxicity compared to compound drugs; therefore hold the promise to be developed as innovative cancer therapeutics. Our long-term goal is to combine our understanding of tumor initiation and metastasis with knowledge in multi- disciplinary technology (such as chemistry and bioengineering) to improve clinical medicine and reduce cancer mortality. Transcription Factors In vivo Tumor initiation metastasis Future 1 Novel miRNAs 1 Future 2 In vitro Tumor growth Cell invasion Target Differentiation Genes Drug-resistance Preclinical Biomarkers Therapeutics 2 A schematic figure of aims: (1) to characterize and validate miRNA candidate functions, (2) to identify miRNA targets and their importance in BTICs and metastasis, (Future 1) transcriptional regulation of miRNAs by transcriptional factors, and (Future 2) preclinical studies of miRNAs and genes serving as novel biomarkers and/or therapeutic targets for breast cancer.

建议：确定调节乳腺肿瘤转移的mirna和基因网络