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The inhibitory network between EZH2 and PARP1 in triple-negative breast cancer

三阴性乳腺癌中 EZH2 和 PARP1 之间的抑制网络

基本信息

批准号：
9906862
负责人：
Qi Cao
金额：
$ 36.94万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2017-03-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906862
关键词：
Advanced Malignant Neoplasm Affect American Attention BMI1 gene BRCA1 gene BRCA2 gene Biological Assay Breast Cancer Cell Breast Cancer Patient Breast Carcinoma Breast Epithelial Cells Cancer Etiology Cell Line Cell Maintenance Cells Cessation of life ChIP-seq Chromosomal Instability Clinical Clinical Trials Complex Core Protein DNA Damage DNA Repair DNA Repair Enzymes DNA Repair Gene DNA Repair Pathway Data Data Set Defect Development Diagnosis Drug Combinations EZH2 gene Environmental Risk Factor Epigenetic Process Feedback GATA4 gene Gene Expression Genes Growth Histone H3 Histones Impairment In Vitro Invaded Lead Lysine Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mass Spectrum Analysis Mediating Metastatic breast cancer Methylation Microarray Analysis Modification Molecular Morbidity - disease rate Neoplasm Metastasis Oncogenic Oncoproteins Organ Outcome Pathway interactions Patients Play Poly(ADP-ribose) Polymerases Polycomb Post-Translational Protein Processing Proteins Regimen Regulation Reporting Role STAT3 gene Site Therapeutic Tissue Microarray Transcript Tumor-Derived Woman Xenograft Model advanced breast cancer breast cancer progression cDNA Arrays cancer biomarkers cancer initiation cancer type gene repression genomic locus inhibitor/antagonist insight knock-down loss of function malignant breast neoplasm member mortality mutant non-histone protein novel novel therapeutics overexpression preclinical study prognostic value protein H(3)recruit response stem cells systemic toxicity targeted treatment therapeutic target triple-negative invasive breast carcinoma tumor growth tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT Breast cancer remains the leading cause of cancer-related death in American women. It is estimated that over 240,000 new breast cancer patients will be diagnosed, and approximately 40,000 patients will die each year in the U.S. Breast cancer is characterized by uncontrolled growth of breast epithelial cells, which can detach, migrate, and invade to other organs causing metastasis. However, the molecular mechanisms of breast cancer are not yet fully understood. One subtype of metastatic breast cancer, triple negative breast cancer (TNBC), is the most aggressive and the most difficult to treat. Therefore, development of new treatments is important in eliminating the mortality and morbidity associated with metastatic breast cancer. Breast cancer develops due to dysregulated gene expression, dysfunctional DNA-damage repair pathways, and is also affected by environmental factors, which epigenetically regulate gene expression and DNA repair pathways. Epigenetic modifiers, such as Polycomb group (PcG) proteins, are crucial in cancer initiation, progression, and metastasis by modifying histones and non-histone proteins. One member of the Polycomb Repressive Complex 2 (PRC2), EZH2, specifically methylates histone H3 protein at lysine 27 to regulate gene expression and is upregulated in invasive breast carcinomas and metastatic breast cancer. High expression levels of EZH2 are strongly associated with poor clinical outcomes in breast cancer patients. The DNA repair protein, PARP1, is also upregulated in breast cancer, but PARP1 inhibitors have been limited to BRCA1 and/or BRCA2 (Breast Cancer 1 or 2)-deficient breast cancer patients (5-10% of all breast cancer cases). EZH2 can actually impair DNA damage repair. However, whether EZH2 and other members of PRC2 regulate PARP1 is unknown. Therefore, the central hypothesis of this proposal is that PRC2 proteins methylate PARP1 lysines, repressing DNA repair activity, and act as PARP1 co-factors in TNBC and the DNA damage response by recruiting PARP1 to genomic loci. Overexpression of EZH2 and PARP1 together may promote TNBC progression, and inhibition of both EZH2 and PARP1 may benefit TNBC patients. Aim 1 will determine whether PRC2 proteins directly interact with PARP1, methylate lysines of PARP1, and repress its activity. The preliminary data strongly suggests that PRC2 proteins and PARP1 coordinate their expression and oncogenic function in TNBC. Therefore, how this complex regulatory network operates between PRC2 and PARP1 and whether this network contributes to the progression of TNBC through DNA repair mechanisms will be investigated (Aim 2). In addition, combined inhibition of EZH2 and PARP1, using commercially available inhibitors, may synergistically and significantly reduce TNBC than either single agent alone (Aim 3). Although the focus of this proposal is to target TNBC, this type of therapy could lead to a breakthrough for other subtypes of breast cancer as well and can have a global impact on ending breast cancer.

项目总结/文摘