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Determine the Functional Role Dub3 in Breast Cancer Progression and Metastasis

确定 Dub3 在乳腺癌进展和转移中的功能作用

基本信息

批准号：
8895123
负责人：
Binhua P Zhou
金额：
$ 35.71万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8895123
关键词：
Address Biological Markers Brain Breast Breast Cancer Cell Breast cancer metastasis Cell Line Cells Chromatin Clinical Coupled Data Deubiquitination Development Diagnosis Diagnostic Disease Distant Metastasis Drosophila genus E-Cadherin ERG gene Embryonic Development Environment Enzymes Epithelial Event Exposure to Genes Goals Growth Human Inflammatory Intrinsic factor Investigation Knock-out Knowledge Libraries Location Lung MCF7 cell Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mesenchymal Metabolic Metastatic breast cancer Modeling Molecular Mus Neoplasm Metastasis Oncologist Pathologist Pharmaceutical Preparations Phase Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Prognostic Marker Property Proteins Public Health Reagent Recording of previous events Recruitment Activity Recurrence Regulation Research Role Sampling Signal Transduction Site Small Interfering RNA Snails Specimen Stromal Neoplasm Structural Biologist Structure T47D Testing Therapeutic Tissues Treatment Efficacy Tumor Cell Invasion Ubiquitination Validation Wound Healing Xenograft procedure aerobic glycolysis base beta-Transducin Repeat-Containing Proteins cancer stem cell cancer therapy cell growth regulation cell motility cytokine epithelial to mesenchymal transition functional plasticity gastrulation in vivo inhibitor/antagonist innovation loss of function macrophage malignant breast neoplasm multidisciplinary neoplastic cell new therapeutic target novel strategies outcome forecast overexpression prevent prognostic value programs promoter public health relevance research study screening success targeted treatment therapy resistant tumor tumor microenvironment tumor progression ubiquitin-protein ligase virtual young woman

项目摘要

DESCRIPTION (provided by applicant): Basal-like breast cancer (BLBC) presents with an aggressive clinical history, development of recurrence, distant metastasis, shorter survival, and usually occurs in young women. BLBC has an activated epithelial-mesenchymal transition (EMT) program, which provides cells with the increased phenotypic and cellular plasticity required during embryonic development, tissue remodeling, wound healing and metastasis. Our long-term goal is to discover the molecular circuitry that governs the functional plasticity of BLBC cells in metastasis and to identify molecules that may serve as druggable targets for treating this deadly disease. In the last nine years, we have systematically studied the function of Snail and the molecular mechanism by which Snail represses E-cadherin expression in BLBC. Our studies clearly indicate that Snail levels are regulated predominantly through protein ubiquitination. High levels of Snail, due to protein stabilization, contribute significantly to the increased invasion, therapeutic resistance, CSC-like properties, and tumor recurrence. However, the mechanism by which Snail escapes ubiquitination and degradation remains unknown; uncovering this mechanism is crucially important for the development of novel approaches to treat BLBC. Recently, we discovered that Dub3 is a bona fide deubiquitinase of Snail and contributes to Snail stabilization in breast cancer. Dub3 is evolutionarily conserved from Drosophila to humans. Dub3-knockout downregulated Snail and disrupted gastrulation (an event that requires EMT) in Drosophila. Elevated expression of Dub3 correlates unequivocally with Snail expression in BLBC samples and cell lines. Overexpression of Dub3 in luminal breast tumor MCF7 and T47D cell lines, which contain no detectable endogenous Dub3 and Snail, induces transformation to a basal-like phenotype; whereas, Dub3-knockdown downregulates Snail and suppresses cell migration. Intriguingly, Dub3 was an early response gene that appeared after exposure to inflammatory cytokines. We hypothesize that Dub3 is the long-sought "missing molecule" that regulates cellular plasticity by controlling the level of Snail durig EMT and metastasis. The objective of this proposal is to characterize the function and regulation of the Dub3-Snail axis and explore the clinical value of Dub3 as a prognostic biomarker and a druggable target for treating metastatic breast cancer. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to delineate th molecular mechanism by which Dub3 controls EMT; (2) to determine the function and regulation of Dub3 in breast cancer; and (3) to define the function and therapeutic efficacy of Dub3 in vivo. Our proposal is innovative and significant, because it will not only uncover a new paradigm that significantly increases our understanding of the regulation of cellular plasticity during tumor progression and metastasis but also leads to the development of specific Dub3 inhibitors for treating metastatic breast cancer.