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.

项目概要/摘要乳腺癌仍然是美国女性癌症相关死亡的主要原因。估计超过24万名新乳腺癌患者将被诊断出来，每年约有4万名患者将死亡今年在美国乳腺癌的特点是乳腺上皮细胞不受控制的生长，这可以分离、迁移和侵入其他器官引起转移。然而，其分子机制乳腺癌尚未完全了解。转移性乳腺癌的一种亚型，三阴性乳腺癌癌症（TNBC）是最具侵袭性且最难治疗的癌症。因此，开发新治疗对于消除与转移性乳腺癌相关的死亡率和发病率非常重要。乳腺癌的发生是由于基因表达失调、DNA 损伤修复途径功能失调、并且还受到环境因素的影响，这些因素通过表观遗传调节基因表达和DNA修复途径。表观遗传修饰剂，例如多梳族 (PcG) 蛋白，对于癌症的发生至关重要，通过修饰组蛋白和非组蛋白来促进进展和转移。 Polycomb 成员之一抑制复合物 2 (PRC2)，EZH2，在赖氨酸 27 处特异性甲基化组蛋白 H3 蛋白以调节基因表达并在浸润性乳腺癌和转移性乳腺癌中上调。高表达 EZH2 水平与乳腺癌患者不良临床结果密切相关。 DNA修复蛋白质 PARP1 在乳腺癌中也表达上调，但 PARP1 抑制剂仅限于 BRCA1 和/或 BRCA2（乳腺癌 1 或 2）缺陷型乳腺癌患者（占所有乳腺癌病例的 5-10%）。 EZH2可以实际上会损害DNA损伤的修复。然而，EZH2 和 PRC2 的其他成员是否监管 PARP1 尚不清楚。未知。因此，该提案的中心假设是 PRC2 蛋白甲基化 PARP1 赖氨酸，抑制 DNA 修复活性，并作为 TNBC 和 DNA 损伤反应中的 PARP1 辅助因子将 PARP1 招募到基因组位点。 EZH2 和 PARP1 一起过度表达可能促进 TNBC EZH2 和 PARP1 的进展和抑制可能有益于 TNBC 患者。目标 1 将确定是否 PRC2 蛋白直接与 PARP1 相互作用，甲基化 PARP1 的赖氨酸，并抑制其活性。这初步数据强烈表明 PRC2 蛋白和 PARP1 协调其表达和致癌作用在 TNBC 中发挥作用。因此，这个复杂的监管网络如何在 PRC2 和 PARP1 之间运作以及该网络是否通过 DNA 修复机制促进 TNBC 的进展将是调查（目标 2）。此外，联合抑制EZH2和PARP1，使用市售的抑制剂，与单独使用任何一种药物相比，可以协同并显着减少 TNBC（目标 3）。虽然该提案的重点是针对 TNBC，这种疗法可能会为其他疗法带来突破乳腺癌的亚型，并且可以对结束乳腺癌产生全球影响。