ERβ repurposes EZH2 to suppress oncogenic NFκB signaling in TNBC

项目摘要/摘要 乳腺癌仍然是女性最常被诊断的癌症，也是第二大致癌原因。 女性中与癌症相关的死亡。三重阴性乳腺癌(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，占 与癌症相关的发病率和死亡率比例高得不成比例。治疗方案包括 对TNBC患者和最常用的新佐剂和佐剂极其有限 化疗药物已经存在了几十年。从头开始和获得性化疗耐药仍然是 重大问题和疾病复发导致绝大多数患者与乳腺癌相关的死亡。 使TNBC的临床管理进一步复杂化的是，缺乏FDA批准的靶向治疗，可以 在佐剂环境中用于防止疾病复发。因此，小说的识别和验证 药物靶点和更有效的治疗选择仍然是一个尚未得到满足的主要临床需求。我们有 研究表明，雌激素受体β(ERβ)在大约20%的TNBCs中表达，并具有 提示ERβ阳性肿瘤患者的远期预后有所改善。此外，我们还展示了 配体介导的ERβ被雌激素或ERβ选择性激动剂激活，抑制肿瘤细胞系和 患者来源的异种移植在体外的增殖、侵袭和迁移，以及原发肿瘤的生长和转移 体内转移性扩散。重要的是，我们提供了第一个证据，表明雌二醇可以在 ERβ阳性的转移性和化疗耐药的患者。从机制上，我们证明了ERβ 有效地抑制核因子-kappaB(核因子-κ-B)途径，这种作用是由 通过ERβ与EZH2/PrC2的结合导致对NFκB的组蛋白残基进行表观遗传修饰 靶基因座。此外，我们还证明了ERβ可以改变化疗的反应性。 TNBC细胞系模型和患者衍生的有机化合物，并抑制耐药细胞系。基于这些 数据，这一建议的中心假设是ERβ重新利用EZH2来抑制TNBC中的NFκB信号 从而产生抗癌作用，增强化疗反应性。为了检验这一假设， 具体目标有：1)。确定ERβ抑制的分子机制 核因子κB在肿瘤细胞中的信号传导和2)。阐明ER-β介导的生物学意义和临床意义 应用新型基因工程小鼠、pDX/pDO模型和基因工程技术抑制肿瘤细胞中的NF-κB信号 病人样本。为了实现这些目标，我们将利用多种模式系统、创新方法和 分子工具，来全面解决我们关注的假说。考虑到在过去几年中 对于患有TNBC的妇女，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.