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

项目总结/摘要 乳腺癌仍然是美国妇女癌症相关死亡的主要原因。据估计 超过240，000名新的乳腺癌患者将被诊断出来，大约40，000名患者将死亡， 乳腺癌的特征是乳腺上皮细胞的不受控制的生长， 脱落、迁移和侵入其他器官，引起转移。然而， 乳腺癌目前还没有被完全了解。转移性乳腺癌的一种亚型，三阴性乳腺癌 癌症（TNBC）是最具侵略性和最难治疗的。因此，开发新的 治疗对于消除与转移性乳腺癌相关的死亡率和发病率是重要的。 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，这些环境因素在表观遗传学上调节基因表达和DNA修复 途径。表观遗传修饰剂，如Polycomb组（PcG）蛋白，在癌症发生中至关重要， 进展和转移。Polycomb的成员之一 抑制复合物2（PRC 2），EZH 2，特异性甲基化组蛋白H3蛋白的赖氨酸27，以调节基因表达。 在浸润性乳腺癌和转移性乳腺癌中表达上调。高表达 EZH 2水平与乳腺癌患者的不良临床结果密切相关。DNA修复 蛋白质PARP 1在乳腺癌中也上调，但PARP 1抑制剂仅限于BRCA 1和/或 BRCA 2（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%）。EZH 2可以 会损害DNA损伤修复然而，EZH 2和PRC 2的其他成员是否调节PARP 1， 未知因此，该提议的中心假设是PRC 2蛋白甲基化PARP 1赖氨酸， 抑制DNA修复活性，并在TNBC和DNA损伤反应中作为PARP 1辅助因子， 将PARP 1募集到基因组位点。EZH 2和PARP 1共同过表达可促进TNBC EZH 2和PARP 1两者的抑制可有益于TNBC患者。目标1将决定是否 PRC 2蛋白直接与PARP 1相互作用，甲基化PARP 1的赖氨酸，并抑制其活性。的 初步数据强烈提示PRC 2蛋白和PARP 1协调它们的表达， 在TNBC中发挥作用。因此，这个复杂的调控网络如何在PRC 2和PARP 1之间运作， 该网络是否通过DNA修复机制有助于TNBC的进展， 研究（目标2）。此外，使用可商购获得的EZH 2和PARP 1的组合抑制， 抑制剂可以协同地和显著地减少TNBC，而不是单独的单一药剂（目的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突破 乳腺癌的亚型，并可能对终止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.