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:
    10059181
  • 负责人:
  • 金额:
    $ 45.64万
  • 依托单位:
  • 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

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.
虽然转移是乳腺癌(BC)最致命的特征,但我们对乳腺癌转移的理解是, 控制这一事件的分子机制仍然不完整。有趣的是,许多BC传播时间很长, 在原发肿瘤出现症状之前事实上,约50%的女性被诊断患有小肿瘤, 乳房(4 mm)在其骨髓中已经具有播散的癌细胞。而且这些 微转移瘤在再次出现时由于无法治愈而潜伏数年而逃避临床检测 继发性肿瘤对最初对原发性肿瘤有效的化疗不敏感。 根除BC的一个主要障碍反映了对乳腺肿瘤如何获得的知识的缺乏。 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 潜伏性微转移这些知识的缺乏对于三阴性乳腺癌来说尤其成问题 (TNBCs),具有高度侵袭性,易于快速复发;它们也缺乏FDA批准的靶向 治疗,以提高他们的总体生存率。长链非编码RNA(lncRNA) 作为染色质重塑和基因表达的强有力的全球调节剂, 生理环境,包括细胞和组织稳态,胚胎发生和发育。而且安 与人类疾病中lncRNA的病理生理学相关的科学证据不断增加, 假设发育和进展中的TNBC劫持了细胞的整体染色质重编程能力, lncRNA,从而引发转移潜伏期的出现并引发致死性疾病复发。 因此,我们鉴定了博格(BMP/OP-应答基因(博格)),作为一种强大的致癌lncRNA,其 异常表达与获得EMT(上皮-间质转化)和转移相关, (a)人和鼠TNBC细胞;(B)人乳腺肿瘤及其相应CNS中的表型 (c)与正常乳腺癌相比,人BC的患者来源的异种移植物(PDX)模型 上皮细胞此外,博格足以驱动潜伏的弥散性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, 抑制细胞衰老程序和激活细胞存活程序。基于这些和其他 初步研究结果,我们假设博格通过(i)重塑TNBC转移和复发, 表观基因组重新激活增殖程序,规避静止和衰老相关 转录组,和(ii)促进诱导生存信号系统耦合到收购 耐药表型这些假设将通过两个具体目标来解决。目标1将决定 博格:TRIM 28复合物形成并驱动TNBC转移和复发的机制。我们将 鉴定结合TRIM 28所必需的最小博格决定簇,以及TRIM 28中结合TRIM 28的结构域。 博格。此外,我们将通过进行TRIM 28和 在BORG熟练和缺乏的TNBC中的H3 K4 me 1 ChIP-seq分析,将在人类中验证的发现 乳腺癌标本目的2将确定博格:RPA 1复合物和NF-κ B的作用机制。 促进TNBC存活和化学抗性。与目标1类似,我们将识别最小博格序列 这是结合RPA 1所必需的,相反,RPA 1中与博格相互作用的区域。预防的影响 将确定博格:RPA 1复合物形成对TNBC存活率和化学抗性的影响, 当与博格结合时,ATM调节TRIM 28和RPA 1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性的事件, 治疗试验总的来说,在这种创新应用中获得的发现将提供新的分子见解 博格如何驱动TNBC获得转移性,复发性和耐药性表型。

项目成果

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William Schiemann其他文献

William Schiemann的其他文献

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{{ truncateString('William Schiemann', 18)}}的其他基金

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
  • 批准号:
    10524737
  • 财政年份:
    2018
  • 资助金额:
    $ 45.64万
  • 项目类别:
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
  • 批准号:
    10302975
  • 财政年份:
    2018
  • 资助金额:
    $ 45.64万
  • 项目类别:
c-Abl-mediated Suppression of Breast Cancer Development and Metastasis
c-Abl 介导的乳腺癌发展和转移抑制
  • 批准号:
    8524287
  • 财政年份:
    2013
  • 资助金额:
    $ 45.64万
  • 项目类别:
c-Abl-mediated Suppression of Breast Cancer Development and Metastasis
c-Abl 介导的乳腺癌发展和转移抑制
  • 批准号:
    9246980
  • 财政年份:
    2013
  • 资助金额:
    $ 45.64万
  • 项目类别:
c-Abl-mediated Suppression of Breast Cancer Development and Metastasis
c-Abl 介导的乳腺癌发展和转移抑制
  • 批准号:
    9040109
  • 财政年份:
    2013
  • 资助金额:
    $ 45.64万
  • 项目类别:
c-Abl-mediated Suppression of Breast Cancer Development and Metastasis
c-Abl 介导的乳腺癌发展和转移抑制
  • 批准号:
    8661715
  • 财政年份:
    2013
  • 资助金额:
    $ 45.64万
  • 项目类别:
Integrin-Mediated Regulation of TGF-Beta Signaling and Tumorigenesis
整合素介导的 TGF-β 信号传导和肿瘤发生的调节
  • 批准号:
    7298058
  • 财政年份:
    2007
  • 资助金额:
    $ 45.64万
  • 项目类别:
Integrin-Mediated Regulation of TGF-Beta Signaling and Tumorigenesis
整合素介导的 TGF-β 信号传导和肿瘤发生的调节
  • 批准号:
    7467406
  • 财政年份:
    2007
  • 资助金额:
    $ 45.64万
  • 项目类别:
Integrin-Mediated Regulation of TGF-Beta Signaling and Tumorigenesis
整合素介导的 TGF-β 信号传导和肿瘤发生的调节
  • 批准号:
    7628064
  • 财政年份:
    2007
  • 资助金额:
    $ 45.64万
  • 项目类别:
Integrin-mediated Regulation of TGFbeta Signaling and Tumorigenesis
整合素介导的 TGFbeta 信号传导和肿瘤发生的调节
  • 批准号:
    8883400
  • 财政年份:
    2007
  • 资助金额:
    $ 45.64万
  • 项目类别:

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