ERβ repurposes EZH2 to suppress oncogenic NFκB signaling in TNBC

ERβ 重新利用 EZH2 抑制 TNBC 中的致癌 NFκB 信号传导

• 批准号: 10540349
• 负责人: John R. Hawse
• 金额: $ 50.63万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540349
• 关键词: Address; Adjuvant; Adjuvant Chemotherapy; Affect; Agonist; Antibodies; Architecture; Biological; Biological Markers; Biological Models; Biology; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Etiology; Cell Line; Cessation of life; Characteristics; Chemoresistance; Chemotherapy-Oncologic Procedure; Chromatin; Clinical; Clinical Management; Complex; DNA Binding; Data; Development; Disease; Disease Management; ERBB2 gene; EZH2 gene; Enhancers; Epidermal Growth Factor Receptor; Epigenetic Process; Estradiol; Estradiol Receptors; Estrogen Receptor alpha; Estrogen Receptor beta; FDA approved; Foundations; Gene Expression Profile; Genetically Engineered Mouse; Goals; Histones; In Vitro; Individual; Invaded; Knowledge; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Modification; Molecular; Morbidity - disease rate; NF-kappa B; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Newly Diagnosed; Oncogenic; Organoids; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Primary Neoplasm; Progesterone Receptors; Prognosis; Prognostic Marker; Proliferating; Proteins; Recurrence; Recurrent disease; Refractory; Resistance; Retrospective cohort; Role; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Treatment Protocols; Tumor Promotion; United States; Validation; Woman; anti-cancer; cancer diagnosis; cancer type; chemotherapy; clinically significant; combat; effective therapy; efficacy evaluation; genetic corepressor; genome-wide; genomic locus; improved; improved outcome; in vitro Model; in vivo; innovation; malignant breast neoplasm; migration; molecular subtypes; mortality; neoplastic cell; new therapeutic target; novel; novel strategies; participant enrollment; patient derived xenograft model; patient stratification; phase II trial; predict responsiveness; prevent; prospective; receptor; response; standard of care; targeted agent; targeted treatment; therapy outcome; tool; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

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.

项目摘要/摘要 乳腺癌仍然是女性中最常见的癌症，是 女性与癌症有关的死亡。三重阴性乳腺癌（TNBC）影响约15-20％ 所有乳腺癌患者，是乳腺癌最具侵略性的亚型，占 与癌症相关的病态性和死亡率的比例不成比例。治疗选择是 对于TNBC患者和最常见的新辅助和调整非常有限 化学疗法药物已经存在数十年。从头开始，获得的化疗耐药性仍然是 大多数患者的主要问题和疾病复发导致乳腺癌相关的死亡。 进一步使TNBC的临床管理复杂化的是缺乏FDA批准的靶向疗法 可用于预防调整环境中的疾病复发。那是新颖的识别和验证 药物靶标和更有效的治疗选择继续代表了主要未满足的临床需求。我们有 证明雌激素受体β（ERβ）在大约20％的TNBC中表达，并且具有 表明ERβ阳性肿瘤患者的长期预后改善。此外，我们已经显示 配体介导的ERβ通过雌二醇或ERβ选择性激动剂激活，抑制了TNBC细胞系和 患者在体外衍生出异种移植的增殖，侵袭和迁移，以及原发性肿瘤的生长和 转移性在体内传播。重要的是，我们提供了第一个证据，表明雌二醇可以在 ERβ阳性转移性和化学难治性TNBC患者。从机械上讲，我们证明了ERβ 强大地抑制TNBC细胞中的核因子Kappa B（NFκB）途径，介导的效果 通过ERβ与EZH2/PRC2的关联，导致对NFκB的组蛋白残留的表观遗传修饰 靶基因基因座。此外，我们已经证明ERβ修改了化学疗法的反应性 TNBC细胞系模型和患者衍生的器官，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重新抑制EZH2抑制TNBC中NFκB信号传导 从而引起抗癌作用并增强化学治疗反应性。为了检验这一假设， 提出了以下特定目标：1）。确定ERβ抑制的分子机制 TNBC和2）中的NFκB信号传导。阐明ERβ介导的生物学重要性和临床意义 使用新型的基因工程小鼠，PDX/PDO模型和 患者标本。为了实现这些目标，我们将利用多种模型系统，创新的方法和 分子工具，以全面解决我们的集中假设。鉴于结果极差 具有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策略。