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

项目摘要/摘要 乳腺癌仍然是美国女性癌症相关死亡的主要原因。据估计， 超过24万名新的乳腺癌患者将被诊断出来，每个患者将有大约4万人死亡 在美国，乳腺癌的特点是乳房上皮细胞不受控制地生长，这可以 分离、迁移和侵袭到其他器官导致转移。然而，其分子机制尚未完全阐明。 人们对乳腺癌的了解还不完全。转移性乳腺癌的一个亚型，三阴性乳房 癌症(TNBC)，是最具侵袭性和最难治疗的疾病。因此，发展新的 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。 乳腺癌的发生是由于基因表达失调，DNA损伤修复途径功能失调， 也受到环境因素的影响，环境因素通过表观遗传方式调节基因表达和DNA修复 小路。表观遗传修饰物，如聚梳组(PcG)蛋白，在癌症的启动过程中起着至关重要的作用， 通过修饰组蛋白和非组蛋白的进展和转移。Polcomb的一名成员 抑制复合体2(PRC2)，EZH2，特异性甲基化组蛋白H3蛋白的27位赖氨酸，以调节基因 在浸润性乳腺癌和转移性乳腺癌中表达上调。高表达 EZH2水平与乳腺癌患者不良的临床结果密切相关。DNA修复 PARP1蛋白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)缺陷的乳腺癌患者(占所有乳腺癌病例的5%-10%)。EZH2可以 实际上损害了DNA损伤修复。然而，EZH2和PRC2的其他成员是否监管PARP1是 未知。因此，这一提议的中心假设是PRC2蛋白甲基化PARP1赖氨酸， 抑制DNA修复活性，并在TNBC和DNA损伤反应中作为PARP1辅助因子 将PARP1招募到基因组座位。EZH2和PARP1共同过表达可能促进TNBC EZH2和PARP1的进展和抑制可能使TNBC患者受益。目标1将决定是否 PRC2蛋白直接与PARP1，PARP1的甲基化赖氨酸相互作用，并抑制其活性。这个 初步数据有力地表明，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在PRC2和PARP1之间是如何运作的，以及 这个网络是否通过DNA修复机制促进TNBC的进展将是 调查(目标2)。此外，使用商用的EZH2和PARP1的联合抑制 与单独使用任何一种药物相比，两种药物均可协同显著降低TNBC(目标3)。虽然 这项建议的重点是针对TNBC，这种类型的治疗可能会导致其他 它也是乳腺癌的亚型，并可对终结乳腺癌产生全球影响。

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.