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.

项目摘要 /摘要 浸润性小叶癌（ILC）是乳腺癌的研究亚型。临床和流行病学 ILC的特征与对雌激素和雌激素受体α（ER）的精致依赖性一致 ILC生物标志物建议患者应在抗雌激素治疗方面取得良好的结果。然而， 最近的研究表明，相对于其他乳腺癌，ILC患者的长期结局较差， 对抗雌激素治疗的反应较差，也不会受益于化学疗法。新疗法是 需要改善ILC患者预后。但是，由于根本缺乏，阻碍了进步 了解ILC的独特生物学，尤其是关于ER信号传导的理解。我们和其他人确定 ILC模型中Novo抗雌激素的耐药性，并发现ILC细胞中的ER被他莫昔芬和下一步激活 一代ER拮抗剂。基于这些观察结果，抗雌激素在治疗ILC中的有限疗效 可能是由于ILC中ER功能的差异所致。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，部分解释了内分泌 反应和阻力。作为这些独特的ER功能和ILC中抗雌激素耐药性的基础，我们 鉴定出DNA损伤检查点1（MDC1）的介质是ILC中ER的新型转录共同调节剂 细胞。 MDC1是DNA损伤反应的基石，但在ILC中，MDC1充当ER共同调节器，IS ER驱动的生长和ER调节主要靶基因以及抗雌激素耐药性所必需的。我们的 数据表明，MDC1至少通过表观基因组重塑至少部分调节ER。 MDC1 ER共同调节器 功能与MDC1在DNA损伤响应中的典型作用相互作用，暗示了这些功能 ILC中的临床化学抗性。该建议的目的是定义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 关键的ER共同调节剂介导ILC中的ER靶基因调节，在ER之间产生可定位的串扰 和DNA损伤响应。在这项研究中，我们将：i）定义ER和MDC1如何相互作用以构建基因 调节复合物； ii）定义ER和MDC1如何影响其集体基因组相互作用； iii）定义 与ER和MDC1功能相关的DNA损伤响应。这个项目将导致机械 了解ILC中MDC1驱动的ER功能，并将ILC中ER的唯一功能链接到新的精度 使用DDR抑制剂的治疗策略。定义MDC1的作用也将提供对独特的见解 ILC的ER依赖性病因。该建议将通过识别ER：MDC1来推进MDC1的翻译研究 生物标志物和治疗策略，以针对MDC1相关的DDR依赖性。表征角色 MDC1对于了解ILC患者的ILC生物学和改善结果至关重要。