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

• 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
• 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

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.

项目摘要/摘要 乳腺癌仍然是美国女性与癌症相关死亡的主要原因。据估计 将诊断出超过240,000名新的乳腺癌患者，每个患者大约将死亡 美国乳腺癌的一年的特征是乳腺上皮细胞的生长不受控制，这可以 脱离，迁移并侵入引起转移的其他器官。但是， 乳腺癌尚未完全了解。转移性乳腺癌的一种亚型，三重阴性乳房 癌症（TNBC）是最具侵略性和最难治疗的癌症。因此，发展新 治疗对于消除与转移性乳腺癌相关的死亡率和发病率很重要。 乳腺癌由于基因表达失调，功能失调的DNA破坏修复途径而发展， 并受环境因素的影响，环境因素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Polycomb组（PCG）蛋白，在癌症开始至关重要， 通过修饰组蛋白和非历史蛋白来进行进展和转移。 Polycomb的一个成员 抑制性复合物2（PRC2），EZH2，特异性甲基甲基化的赖氨酸27的组蛋白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的水平与乳腺癌患者的临床结局差密切相关。 DNA修复 蛋白质PARP1在乳腺癌中也被上调，但PARP1抑制剂仅限于BRCA1和/或 BRCA2（乳腺癌1或2）缺乏乳腺癌患者（占所有乳腺癌病例的5-10％）。 Ezh2可以 实际上会损害DNA损伤修复。但是，EZH2和PRC2调节PARP1的其他成员是否是 未知。因此，该提案的中心假设是Prc2蛋白甲基酸PARP1赖氨酸， 抑制DNA修复活性，并充当TNBC中的PARP1副因素，并通过 将PARP1招募到基因组基因局。 EZH2和PARP1的过表达可能会促进TNBC EZH2和PARP1的进展和抑制可能使TNBC患者受益。 AIM 1将确定是否 PRC2蛋白直接与PARP1，PARP1的甲基赖氨酸赖氨酸相互作用，并抑制其活性。这 初步数据强烈表明PRC2蛋白和PARP1协调其表达和致癌性 TNBC的功能。因此，这个复杂的监管网络如何在PRC2和PARP1和PARP1之间运行 该网络是否有助于TNBC通过DNA修复机制的发展 调查（AIM 2）。另外，使用市售的EZH2和PARP1的联合抑制 抑制剂，可能与单独的任何一种药物相比，可以协同和显着降低TNBC（AIM 3）。虽然 该提案的重点是针对TNBC，这种类型的疗法可能会导致其他 乳腺癌的亚型也可能对结束乳腺癌产生全球影响。