MDC1: central regulator of estrogen receptor function and therapy response in lobular carcinoma

MDC1：小叶癌雌激素受体功能和治疗反应的中枢调节因子

• 批准号: 10361108
• 负责人: Matthew J Sikora
• 金额: $ 35.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361108
• 关键词: Address; Affect; Agonist; Antiestrogen Therapy; Automobile Driving; Binding; Biological Markers; Biology; Cessation of life; Chemoresistance; Chromatin; Chromatin Structure; Clinical; Clinical Data; Complex; DNA; DNA Binding; DNA Damage; DNA Repair Gene; DNA Repair Pathway; DNA damage checkpoint; Data; Dependence; Development; Disease; ESR1 gene; Endocrine; Epidemiology; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Therapy; Estrogens; Etiology; Foundations; Functional disorder; Gamma-H2AX; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Goals; Growth; Link; Lobular Carcinoma; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Outcome; Patient Care; Patient-Focused Outcomes; Patients; Precision therapeutics; Proteins; Proteomics; Recurrence; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Tamoxifen; Therapeutic; Tumor Suppressor Proteins; Woman; Work; antagonist; base; cancer invasiveness; cancer subtypes; chemotherapy; epigenomics; hormone therapy; improved; improved outcome; inhibitor; insight; knock-down; malignant breast neoplasm; next generation; novel; novel therapeutic intervention; patient population; predictive marker; protein complex; receptor function; response; scaffold; therapy resistant; transcriptome; translational study; treatment response; treatment strategy

PROJECT SUMMARY / ABSTRACT Invasive lobular carcinoma (ILC) is an understudied subtype of breast cancer. Clinical and epidemiological features of ILC are consistent with an exquisite dependence on estrogen and estrogen receptor alpha (ER), and ILC biomarkers suggest that patients should have good outcomes with anti-estrogen treatment. However, recent studies show that relative to other breast cancers, ILC patients have poorer long-term outcomes, have poorer response to anti-estrogen therapy, and also do not benefit from chemotherapy. New treatments are needed to improve ILC patient outcomes. However, advances are hindered by a fundamental lack of understanding of the distinct biology of ILC, in particular regarding ER signaling. We and others identified de novo anti-estrogen resistance in ILC models, and see that ER in ILC cells is activated by tamoxifen and next- generation ER antagonists. Based on these observations, the limited efficacy of anti-estrogens in treating ILC may be due to differences in ER function in ILC. Our work has identified unique ER functions in ILC, including ILC-specific ER target genes, ER DNA binding, and ER signaling pathways, which in part explain endocrine response and resistance. As a basis for these unique ER functions and anti-estrogen resistance in ILC, we identified mediator of DNA damage checkpoint 1 (MDC1) as a novel transcriptional co-regulator of ER in ILC cells. MDC1 is a cornerstone of DNA damage response, but in ILC, MDC1 acts as an ER co-regulator and is required for ER-driven growth and ER regulation of key target genes, as well as anti-estrogen resistance. Our data indicate that MDC1 regulates ER at least in part through epigenomic remodeling. MDC1 ER co-regulator functions interplay with canonical roles of MDC1 in DNA damage response, implicating these functions in clinical chemoresistance in ILC. The objective of this proposal is to define how MDC1 controls ER-driven gene regulation and how ER:MDC1 mediates DDR functions in ILC cells. Our central hypothesis is that MDC1 is a critical ER co-regulator mediating ER target gene regulation in ILC, creating targetable cross-talk between ER and DNA damage response. In this study, we will: i) Define how ER and MDC1 interact to build a gene regulation complex; ii) Define how ER and MDC1 influence their collective genome interactions; iii) Define the DNA damage response that is associated with ER and MDC1 function. This project will lead to mechanistic understanding of MDC1-driven ER functions in ILC, and link the unique functions of ER in ILC to new precision treatment strategies using DDR inhibitors. Defining the role of MDC1 will also provide insight into the unique ER-dependent etiology of ILC. This proposal will advance translational study of MDC1 by identifying ER:MDC1 biomarkers and therapeutic strategies to target MDC1-related DDR dependencies. Characterizing the role of MDC1 is critical to understand ILC biology and improve outcomes for patients with ILC.

项目概要/摘要 浸润性小叶癌（ILC）是一种尚未被研究的乳腺癌亚型。临床和流行病学 ILC 的特征与对雌激素和雌激素受体 α (ER) 的严格依赖一致， ILC 生物标志物表明，患者接受抗雌激素治疗应该会获得良好的结果。然而， 最近的研究表明，相对于其他乳腺癌，ILC 患者的长期预后较差， 对抗雌激素治疗的反应较差，并且也不能从化疗中获益。新的治疗方法是 需要改善 ILC 患者的治疗效果。然而，由于根本性的缺乏，进展受到阻碍。 了解 ILC 的独特生物学，特别是有关 ER 信号传导的知识。我们和其他人确定了 novo 在 ILC 模型中进行抗雌激素抵抗，发现 ILC 细胞中的 ER 被他莫昔芬激活，接下来- 一代 ER 拮抗剂。基于这些观察，抗雌激素治疗 ILC 的疗效有限 可能是由于 ILC 中 ER 功能的差异所致。我们的工作确定了 ILC 中独特的 ER 功能，包括 ILC 特异性 ER 靶基因、ER DNA 结合和 ER 信号通路，部分解释了内分泌 反应和抵抗。作为 ILC 中这些独特的 ER 功能和抗雌激素耐药性的基础，我们 鉴定 DNA 损伤检查点 1 (MDC1) 介导物为 ILC 中 ER 的新型转录共调节因子 细胞。 MDC1 是 DNA 损伤反应的基石，但在 ILC 中，MDC1 充当 ER 协同调节因子，并且 ER 驱动的生长和关键靶基因的 ER 调节以及抗雌激素抵抗所需。我们的 数据表明 MDC1 至少部分通过表观基因组重塑来调节 ER。 MDC1 ER 协同调节器 功能与 MDC1 在 DNA 损伤反应中的典型作用相互作用，暗示这些功能 ILC 的临床化疗耐药性。该提案的目标是定义 MDC1 如何控制 ER 驱动基因 调节以及 ER:MDC1 如何介导 ILC 细胞中的 DDR 功能。我们的中心假设是 MDC1 是 介导 ILC 中 ER 靶基因调控的关键 ER 共调节因子，在 ER 之间产生可靶向的串扰 和 DNA 损伤反应。在本研究中，我们将： i) 定义 ER 和 MDC1 如何相互作用来构建基因 调节综合体； ii) 定义 ER 和 MDC1 如何影响它们的集体基因组相互作用； iii) 定义 与 ER 和 MDC1 功能相关的 DNA 损伤反应。该项目将导致机械化 了解ILC中MDC1驱动的ER功能，并将ILC中ER的独特功能与新的精度联系起来 使用 DDR 抑制剂的治疗策略。定义 MDC1 的角色还将提供对独特的 ILC 的 ER 依赖性病因学。该提案将通过识别 ER:MDC1 来推进 MDC1 的转化研究 针对 MDC1 相关 DDR 依赖性的生物标志物和治疗策略。描述角色的特征 MDC1 对于了解 ILC 生物学和改善 ILC 患者的预后至关重要。