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.

项目总结/摘要 浸润性小叶癌（ILC）是一种研究不足的乳腺癌亚型。临床和流行病学 ILC的特征与对雌激素和雌激素受体α（ER）的高度依赖性一致， ILC生物标志物提示患者抗雌激素治疗应具有良好的结果。然而，在这方面， 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，也不能从化疗中获益。新的治疗方法 需要改善ILC患者的预后。然而，进展受到基本缺乏 了解ILC的独特生物学，特别是关于ER信号传导。我们和其他人发现， 在ILC模型中，新的抗雌激素抵抗，并看到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。我们的工作已经确定了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，这部分解释了内分泌 反应和抵抗。作为ILC中这些独特的ER功能和抗雌激素抵抗的基础，我们 鉴定出DNA损伤检查点1（MDC 1）介导物是ILC中ER的一种新的转录共调节因子 细胞MDC 1是DNA损伤反应的基石，但在ILC中，MDC 1作为ER共调节因子， ER驱动的生长和关键靶基因的ER调节以及抗雌激素抗性所需。我们 数据表明，MDC 1至少部分通过表观基因组重塑来调节ER。MDC 1 ER辅助调节剂 在DNA损伤反应中，MDC 1的功能与MDC 1的典型作用相互作用，暗示这些功能在 ILC的临床耐药性。本提案的目的是确定MDC 1如何控制ER驱动的基因 ER：MDC 1如何在ILC细胞中介导DDR功能。我们的中心假设是，MDC 1是一个 在ILC中介导ER靶基因调控的关键ER辅助调节因子，在ER和ER之间产生靶向串扰， 和DNA损伤反应。在这项研究中，我们将：i）定义ER和MDC 1如何相互作用以构建基因 调控复合物; ii）定义ER和MDC 1如何影响它们的集体基因组相互作用; iii）定义 与ER和MDC 1功能相关的DNA损伤反应。该项目将导致机械化 理解ILC中MDC 1驱动的ER功能，并将ILC中ER的独特功能与新的精度相关联 使用DDR抑制剂的治疗策略。定义MDC 1的角色还将提供对独特的 ILC的ER依赖性病因。该提案将通过鉴定ER：MDC 1来推进MDC 1的翻译研究 靶向MDC 1相关DDR依赖性的生物标志物和治疗策略。角色的特点 MDC 1对于了解ILC生物学和改善ILC患者的预后至关重要。