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Regulation of non-proteolytic ubiquitination in cancer chemoresistance and progression

非蛋白水解泛素化在癌症化疗耐药和进展中的调节

基本信息

批准号：
10407385
负责人：
Erik Knudsen
金额：
$ 38.48万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407385
关键词：
Adjuvant Therapy Affect Animals Biochemical Biological Biological Assay Biological Markers Cell Count Cell Nucleus Cells Chemoresistance Clinical Trials Cytotoxic Chemotherapy DNA Repair Data Development Disease Down-Regulation Drug Targeting Epithelial Exhibits Flow Cytometry Goals Head and Neck Cancer Histologic Human In Vitro Incidence Individual Knowledge Link Lysine Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mammospheres Measures Mediating Mesenchymal Molecular Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Oncogenic Outcome Pathologic Pathway interactions Patients Phenotype Physiological Pluripotent Stem Cells Polyubiquitin Prognostic Marker Property Proteins Public Health Publishing Regulation Relapse Risk Factors Role Scheme Series Signal Pathway Signal Transduction Specificity Subgroup TWIST1 gene Testing The Cancer Genome Atlas Therapeutic Tissues Transgenic Mice Transplantation Ubiquitin Ubiquitination Work Xenograft procedure anti-cancer base breast cancer progression cancer cell cancer stem cell cancer subtypes chemotherapy combat epithelial to mesenchymal transition genetic profiling in vivo inhibitor/antagonist malignant breast neoplasm mortality mouse model mutant new therapeutic target novel novel strategies overexpression personalized medicine predicting response protein degradation protein expression self-renewal stem stem cell expansion stem cell self renewal stemness success therapeutically effective therapy resistant transcription factor treatment response triple-negative invasive breast carcinoma tumor tumor heterogeneity tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

Project Summary Triple-negative breast cancer (TNBC) is a group of aggressive diseases with a greater incidence of relapse, metastasis and patient mortality compared to other breast cancer subtypes. Genetic profiling studies have identified at least six subgroups of TNBC exhibiting distinct molecular features. These subgroup- associated molecular features, or ‘biomarkers’, may eventually be used to predict response to treatment; however, not all biomarkers cause tumor progression and/or treatment resistance. It is therefore critical to better understand the molecular drivers that underlie TNBC subgroups. TNBC expresses abundant Twist, a fundamental and versatile regulator of TNBC progression. Despite being a long-standing drug target, there is no approach to specifically target Twist activity. Ubiquitin is an important regulatory signal. K48-linked ubiquitination causes degradation and downregulation of protein substrates, whereas the newly characterized K63-linked ubiquitination activates protein-mediated signaling pathways. E3 ligases are the substrate recognition protein that impart specificity to the ubiquitin signal. Many E3 ligases are upregulated in human cancers. Several inhibitors that inactivate the oncogenic E3 ligases are currently being tested in clinical trials. By identifying which E3 ligases account for the K63-linked ubiquitination of Twist, we could potentially discover new drug targets that specifically block Twist to treat TNBC. The goal of this application is to characterize the K63-linked ubiquitination network that orchestrates Twist activation and protein expression and to identify the E3 ligases responsible for Twist K63-linked ubiquitination. We will conduct a series of biochemical and biological studies to uncover the mechanisms by which K63-linked ubiquitination regulates Twist activity post-translationally. We will establish the pathological roles of Twist K63-linked ubiquitination and its controlling E3 ligases in animal studies. We will validate the physiological relevance of E3 ligases as functional biomarkers in TNBC tumors and assess whether inhibiting these E3 ligases has therapeutic potential. Relevance to Public Health: Our study characterizing E3 ligases as molecular drivers of TNBC will open the door to developing new strategies for effectively treating TNBC. Through a non-biased E3 ligase screen, we identified two primary Twist-controlling E3 ligases that appear to be present in most TNBC tissues in a mutually exclusive fashion, most likely as the result of tumor heterogeneity. If the two E3 ligases, individually or in combination, do affect TNBC regulation, then they could be used as functional prognosis markers in personalized medicine. Aside from TNBC, the knowledge gained through this work is potentially applicable to other tumor types where Twist activation is implicated, such as prostrate, lung, head and neck cancers.

项目总结