ERβ repurposes EZH2 to suppress oncogenic NFκB signaling in TNBC

项目总结/摘要 乳腺癌仍然是女性中最常见的癌症，也是女性中第二大癌症。 妇女中与癌症有关的死亡。三阴性乳腺癌（TNBC）影响大约15-20%的 所有乳腺癌患者，是乳腺癌中最具侵袭性的亚型， 癌症相关发病率和死亡率的比例不成比例地更高。治疗选择 对于TNBC患者极其有限，并且最常用的新辅助治疗和辅助治疗 化疗药物已经存在了几十年。新生和获得性化疗耐药性仍然是一个 主要问题和疾病复发导致大多数患者的乳腺癌相关死亡。 使TNBC的临床管理进一步复杂化的是缺乏FDA批准的靶向疗法， 用于预防辅助治疗中的疾病复发。因此，鉴定和验证新的 药物靶点和更有效的治疗选择仍然是未满足的主要临床需求。我们有 证实雌激素受体β（ERβ）在大约20%的TNBC中表达，并且具有 ERβ阳性肿瘤患者的长期预后得到改善。此外，我们还表明， 雌二醇或ERβ选择性激动剂对ERβ的配体介导的活化抑制TNBC细胞系， 患者来源的异种移植物的体外增殖、侵袭和迁移，以及原发性肿瘤生长， 体内转移扩散。重要的是，我们提供了第一个证据表明，雌二醇可以引起临床效益， ERβ阳性转移性和化疗难治性TNBC患者。从机制上讲，我们证明ERβ 有效抑制TNBC细胞中的核因子κ B（NFκB）通路， 通过ERβ与EZH 2/PRC 2的结合，导致NFκB处组蛋白残基的表观遗传修饰 靶基因座。此外，我们已经证明ERβ改变了化疗的反应性， TNBC细胞系模型和患者来源的类器官，并抑制化学抗性细胞系。基于这些 数据，该提议的中心假设是ERβ重新利用EZH 2来抑制TNBC中的NFκB信号传导 从而引发抗癌作用并增强化疗反应性。为了验证这个假设， 具体目标如下：1）。确定ERβ抑制 TNBC中的NFκB信号传导和2）。阐明雌激素受体β介导的细胞凋亡的生物学意义和临床意义 使用新型基因工程小鼠、PDX/PDO模型和 病人标本为了实现这些目标，我们将利用多个模型系统，创新方法， 分子工具，来全面解决我们的重点假设。考虑到2010年的 对于患有TNBC的女性，拟议的研究对于改善治疗的目标至关重要 更有效地管理这种疾病的战略。

PROJECT SUMMARY/ABSTRACT Breast cancer remains the most commonly diagnosed cancer in women and is the second leading cause of cancer-related deaths among women. Triple Negative Breast Cancer (TNBC) affects approximately 15-20% of all breast cancer patients, is the most aggressive sub-type of breast cancer and accounts for a disproportionately higher fraction of cancer-related morbidities and mortalities. Treatment options are extremely limited for TNBC patients and the most commonly employed neoadjuvant and adjuvant chemotherapy drugs have existed for decades. De novo and acquired chemotherapy resistance remains a major problem and disease recurrence results in breast cancer-related death for the large majority of patients. Further complicating the clinical management of TNBC is the lack of FDA-approved targeted therapies that can be utilized to prevent disease recurrence in the adjuvant setting. Thus, the identification and validation of novel drug targets and more effective treatment options continues to represent a major unmet clinical need. We have demonstrated that Estrogen Receptor Beta (ERβ) is expressed in approximately 20% of TNBCs, and have shown that patients with ERβ positive tumors have improved long-term prognosis. In addition, we have shown that ligand-mediated activation of ERβ by estradiol, or ERβ selective agonists, inhibits TNBC cell line and patient derived xenograft proliferation, invasion, and migration in vitro, as well as primary tumor growth and metastatic spread in vivo. Importantly, we provide the first evidence that estradiol can elicit clinical benefit in a patient with ERβ positive metastatic and chemo-refractory TNBC. Mechanistically, we demonstrate that ERβ potently suppresses the nuclear factor kappa B (NFκB) pathway in TNBC cells, effects that are mediated through association of ERβ with EZH2/PRC2 leading to epigenetic modifications to histone residues at NFκB target gene loci. Furthermore, we have demonstrated that ERβ modifies chemotherapy responsiveness of TNBC cell line models and patient derived organoids and inhibits chemo-resistant cell lines. Based on these data, the central hypothesis of this proposal is that ERβ repurposes EZH2 to inhibit NFκB signaling in TNBC thereby eliciting anti-cancer effects and enhancing chemotherapeutic responsiveness. To test this hypothesis, the following Specific Aims are proposed: 1). Determine the molecular mechanisms by which ERβ suppresses NFκB signaling in TNBC and 2). Elucidate the biological importance and clinical significance of ERβ-mediated suppression of NFκB signaling in TNBC using novel genetically engineered mice, PDX/PDO models and patient specimens. To conduct these Aims, we will utilize multiple model systems, innovative approaches and molecular tools, to comprehensively address our focused hypothesis. Given the extremely poor outcomes in women with TNBC, the proposed studies are of critical importance towards the goal of improving treatment strategies to more effectively manage this disease.