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.

项目概要/摘要 乳腺癌仍然是女性中最常诊断出的癌症，并且是导致乳腺癌的第二大原因。 三阴性乳腺癌 (TNBC) 影响了大约 15-20% 的女性。 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不成比例地较高。 对于 TNBC 患者和最常用的新辅助和辅助治疗极为有限 化疗药物已经存在了几十年，而获得性化疗耐药性仍然是一个问题。 主要问题和疾病复发导致大多数患者与乳腺癌相关的死亡。 缺乏 FDA 批准的靶向治疗药物使 TNBC 的临床管理进一步复杂化。 因此，新药的鉴定和验证可用于预防疾病复发。 药物靶点和更有效的治疗方案仍然是我们未满足的主要临床需求。 证明雌激素受体β (ERβ) 在大约 20% 的 TNBC 中表达，并且 研究表明，ERβ 阳性肿瘤患者的长期预后有所改善。 通过雌二醇或 ERβ 选择性激动剂配体介导的 ERβ 激活，抑制 TNBC 细胞系 患者来源的异种移植物体外增殖、侵袭和迁移，以及原发性肿瘤的生长和 重要的是，我们提供了第一个证据表明雌二醇可以在体内产生临床益处。 ERβ 阳性转移性且化疗难治性 TNBC 患者从机制上证明 ERβ。 有效抑制 TNBC 细胞中的核因子 kappa B (NFκB) 通路，介导的作用 通过 ERβ 与 EZH2/PRC2 的关联，导致 NFκB 处组蛋白残基的表观遗传修饰 此外，我们已经证明 ERβ 可以改变化疗反应性。 TNBC 细胞系模型和患者衍生的类器官，并以此为基础抑制化疗耐药细胞系。 数据显示，该提案的中心假设是 ERβ 重新利用 EZH2 来抑制 TNBC 中的 NFκB 信号传导 引发抗癌作用并增强化疗反应性从而检验这一假设， 提出以下具体目标： 1) 确定 ERβ 抑制的分子机制。 TNBC 中的 NFκB 信号传导和 2) 阐明 ERβ 介导的生物学重要性和临床意义。 使用新型基因工程小鼠、PDX/PDO 模型和 TNBC 抑制 NFκB 信号传导 为了实现这些目标，我们将利用多种模型系统、创新方法和 分子工具，以全面解决我们的重点假设。 患有 TNBC 的女性，拟议的研究对于改善治疗目标至关重要 更有效地控制这种疾病的策略。