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Role of the lncRNA BORG in Breast Cancer Metastatic Progression and Recurrence

lncRNA BORG 在乳腺癌转移进展和复发中的作用

基本信息

批准号：
10524737
负责人：
William Schiemann
金额：
$ 44.73万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-06 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524737
关键词：
Address Apoptosis Automobile Driving Binding Bone Marrow Breast Cancer Cell Breast Cancer Patient Breast Epithelial Cells Breast cancer metastasis Cause of Death Cell Aging Cell Survival Cells Cellular Stress ChIP-seq Characteristics Chemoresistance Chromatin Clinical Complex Comprehensive Cancer Center Coupled Cytotoxic Chemotherapy DNA Damage Data Detection Development Diagnosis Disease Disseminated carcinoma ERBB2 gene Embryonic Development Epigenetic Process Epithelium Event FDA approved Functional disorder GADD45A gene Gene Expression Genes Goals Homeostasis Hormone Receptor Human In Vitro Induction of Apoptosis Knowledge Length Malignant Epithelial Cell Mammary Gland Parenchyma Mammary Neoplasms Maps Mediating Medical Medicine Mesenchymal Metastatic Neoplasm to the Central Nervous System Metastatic breast cancer Metastatic/Recurrent Micrometastasis Modeling Molecular Monitor Mus NF-kappa B Neoplasm Metastasis Oncogenic Outcome Patient-Focused Outcomes Patients Phenotype Physiological Predisposition Primary Neoplasm Proliferating Protein Kinase Quality of life Recurrence Recurrent Malignant Neoplasm Recurrent disease Relapse Repression Resistance Role Science Signal Transduction Specimen Survival Rate System Therapy trial Time Tissue Microarray Tissues Transcription Repressor Transforming Growth Factor beta Tumorigenicity United States Untranslated RNA Woman breast cancer survival cancer recurrence cancer stem cell chemotherapy chromatin remodeling epigenome epigenomics gene interaction human disease human model improved in vivo innovation insight malignant breast neoplasm mechanotransduction member novel patient derived xenograft model pre-clinical therapy prevent programs response senescence stem cell self renewal stressor symptom management targeted treatment transcriptome triple-negative invasive breast carcinoma tumor

项目摘要

Although metastasis is the most lethal characteristic of breast cancer (BC), our understanding of the molecular mechanisms that govern this event remains incomplete. Interestingly, many BCs disseminate long before their primary tumors become symptomatic. In fact, ~50% of women diagnosed with small tumors of the breast (4 mm) already harbor disseminated carcinoma cells in their bone marrow. Moreover, these micrometastases escape clinical detection by remaining latent for years before reemerging as incurable secondary tumors that are insensitive to chemotherapies that were originally effective against the primary tumor. A major barrier to eradicating BC reflects the paucity of knowledge related to how mammary tumors acquire metastatic and recurrent phenotypes, which underlies the inability of science and medicine to detect and treat latent micrometastases. These knowledge deficits are especially problematic for triple-negative breast cancers (TNBCs), which are highly aggressive and prone to rapid relapse; they also lack FDA-approved targeted therapies necessary to improve their dismal overall survival rates. Long noncoding RNAs (lncRNAs) have recently emerged as powerful global regulators of chromatin remodeling and gene expression in diverse physiological settings, including cell and tissue homeostasis, embryogenesis and development. Moreover, an ever expanding array of scientific evidence related to the pathophysiology of lncRNAs in human disease led us to postulate that developing and progressing TNBCs hijack the global chromatin reprogramming ability of lncRNAs, thereby eliciting emergence from metastatic latency and initiating lethal disease recurrence. Accordingly, we identified BORG (BMP/OP-Responsive Gene (BORG), as a powerful oncogenic lncRNA whose aberrant expression correlated with the acquisition of EMT (epithelial-mesenchymal transition) and metastatic phenotypes in (a) human and murine TNBCs cells; (b) human breast tumors and their corresponding CNS metastases; and (c) patient-derived xenograft (PDX) models of human BC as compared to normal breast epithelial cells. Additionally, BORG is sufficient in driving latent disseminated TNBCs cells to reactivate proliferative programs both in vitro and in vivo, events associated with epigenomic reprogramming operant in repressing cellular senescence programs, and in activating cell survival programs. Based on these and other preliminary findings, we hypothesize that BORG drives TNBC metastasis and recurrence by (i) remodeling the epigenome to reactivate proliferative programs that circumvent quiescence- and senescence-associated transcriptomes, and (ii) promoting the induction of survival signaling systems coupled to the acquisition of chemoresistant phenotypes. These hypotheses will be addressed by two Specific Aims. Aim 1 will determine the mechanisms whereby BORG:TRIM28 complexes form and drive TNBC metastasis and recurrence. We will identify the minimal BORG determinants necessary to bind TRIM28, as well as the domains in TRIM28 that bind BORG. Additionally, we will map the chromatin alterations provoked by BORG by performing TRIM28 and H3K4me1 ChIP-seq analyses in BORG-proficient and -deficient TNBCs, findings that will be validated in human breast cancer specimens. Aim 2 will determine the mechanisms whereby BORG:RPA1 complexes and NF-kB promote TNBC survival and chemoresistance. Similar to Aim 1, we will identify the minimal BORG sequences necessary to bind RPA1, and conversely, the regions in RPA1 that interact with BORG. The impact of preventing BORG:RPA1 complex formation on TNBC survival and chemoresistance will be determined, as will the role of ATM in regulating the interplay between TRIM28 and RPA1 when bound to BORG. Finally, the impact of these events in mediating TNBC resistance to cytotoxic chemotherapy will be assessed in vitro, and in preclinical therapy trials. Collectively, the findings obtained in this innovative application will provide novel molecular insights into how BORG drives TNBC to acquire metastatic, recurrent, and chemoresistant phenotypes.

尽管转移是乳腺癌 (BC) 最致命的特征，但我们对乳腺癌的认识控制这一事件的分子机制仍然不完整。有趣的是，许多BC传播了很长的在他们的原发肿瘤出现症状之前。事实上，大约 50% 的女性被诊断出患有小肿瘤乳房（4毫米）的骨髓中已经含有播散性癌细胞。而且，这些微转移在重新出现为无法治愈之前，会潜伏多年，从而逃避临床检测对最初对原发肿瘤有效的化疗不敏感的继发性肿瘤。根除乳腺癌的一个主要障碍反映了对乳腺肿瘤如何发生相关知识的缺乏转移性和复发性表型，这是科学和医学无法检测和治疗的基础潜在的微转移。这些知识缺陷对于三阴性乳腺癌来说尤其成问题（TNBC），具有高度侵袭性并且容易快速复发；他们还缺乏 FDA 批准的靶向药物改善他们惨淡的总体生存率所必需的治疗。长非编码 RNA (lncRNA) 具有最近成为多种染色质重塑和基因表达的强大全球调节剂生理环境，包括细胞和组织稳态、胚胎发生和发育。此外，一个与人类疾病中 lncRNA 的病理生理学相关的科学证据不断增加，引导我们假设正在发展和进步的 TNBC 劫持了全局染色质重编程能力 lncRNA，从而引发转移潜伏期的出现并启动致命疾病的复发。因此，我们确定了 BORG（BMP/OP 响应基因（BORG））是一种强大的致癌 lncRNA，其异常表达与 EMT（上皮间质转化）和转移相关 (a)人和鼠TNBC细胞的表型； (b) 人类乳腺肿瘤及其相应的中枢神经系统转移； (c) 与正常乳房相比的人类 BC 患者来源的异种移植 (PDX) 模型上皮细胞。此外，BORG 足以驱动潜在播散的 TNBC 细胞重新激活体外和体内的增殖程序，与表观基因组重编程操作相关的事件抑制细胞衰老程序，并激活细胞生存程序。基于这些和其他初步发现，我们假设 BORG 通过以下方式驱动 TNBC 转移和复发：(i) 重塑表观基因组重新激活规避静止和衰老相关的增殖程序转录组，以及（ii）促进与获得相关的生存信号系统的诱导化学抗性表型。这些假设将通过两个具体目标来解决。目标1将决定 BORG:TRIM28 复合物形成并驱动 TNBC 转移和复发的机制。我们将鉴定结合 TRIM28 所需的最小 BORG 决定簇，以及 TRIM28 中结合的结构域博格。此外，我们将通过执行 TRIM28 和在 BORG 充足和缺乏的 TNBC 中进行 H3K4me1 ChIP-seq 分析，这些结果将在人体中得到验证乳腺癌标本。目标 2 将确定 BORG:RPA1 复合物和 NF-kB 的作用机制促进 TNBC 存活和化疗耐药。与目标 1 类似，我们将识别最小的 BORG 序列结合 RPA1 所必需的，相反，RPA1 中与 BORG 相互作用的区域。预防的影响 BORG:RPA1 复合物的形成对 TNBC 存活和化疗耐药性的影响以及其作用将得到确定当与 BORG 结合时，ATM 调节 TRIM28 和 RPA1 之间的相互作用。最后，这些影响将在体外和临床前评估介导 TNBC 对细胞毒性化疗耐药的事件治疗试验。总的来说，这一创新应用中获得的发现将提供新颖的分子见解研究 BORG 如何驱动 TNBC 获得转移性、复发性和化疗耐药表型。