Mechanisms that impact metastatic progression of triple negative breast cancer

影响三阴性乳腺癌转移进展的机制

• 批准号: 10009841
• 负责人: Rajeev S Samant
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009841
• 关键词: Automobile Driving; Biogenesis; Breast Cancer Cell; Breast cancer metastasis; Cell Nucleolus; Cells; Cessation of life; Clinical; Databases; Diagnosis; Disease; Dose; Genetic Transcription; Hypertrophy; Incidence; Investigation; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mesenchymal; Metabolic; Mission; Modeling; Neoplasm Metastasis; Pathologic; Pathway interactions; Patients; Polymerase; Pre-Clinical Model; Proteins; Proteomics; RNA Polymerase I; RNA chemical synthesis; Research; Ribosomal DNA; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Role; Signal Transduction; Site; Small Nucleolar RNA; Specimen; Stains; Subgroup; Survival Rate; Testing; Therapeutic; Time; Tumor Tissue; Veterans; Woman; Women' s Health; Work; active duty; beta catenin; cancer cell; cancer type; chemical genetics; chemotherapy; cohort; design; inhibitor/antagonist; insight; malignant breast neoplasm; mammary; military veteran; military women; mortality; neoplastic cell; new therapeutic target; novel; pre-clinical; prognostic; service member; tool; triple-negative invasive breast carcinoma; tumor; tumor progression; young woman; Automobile Driving; Biogenesis; Breast Cancer Cell; Breast cancer metastasis; Cell Nucleolus; Cells; Cessation of life; Clinical; Databases; Diagnosis; Disease; Dose; Genetic Transcription; Hypertrophy; Incidence; Investigation; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mesenchymal; Metabolic; Mission; Modeling; Neoplasm Metastasis; Pathologic; Pathway interactions; Patients; Polymerase; Pre-Clinical Model; Proteins; Proteomics; RNA Polymerase I; RNA chemical synthesis; Research; Ribosomal DNA; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Role; Signal Transduction; Site; Small Nucleolar RNA; Specimen; Stains; Subgroup; Survival Rate; Testing; Therapeutic; Time; Tumor Tissue; Veterans; Woman; Women' s Health; Work; active duty; beta catenin; cancer cell; cancer type; chemical genetics; chemotherapy; cohort; design; inhibitor/antagonist; insight; malignant breast neoplasm; mammary; military veteran; military women; mortality; neoplastic cell; new therapeutic target; novel; pre-clinical; prognostic; service member; tool; triple-negative invasive breast carcinoma; tumor; tumor progression; young woman

There is a notably high incidence of breast cancer among younger military women (20% to 40% higher). The incident rate of breast cancer for active duty women is seven times higher than the average incident rate of fifteen other cancer types across all service members. An estimated 90% of deaths due to breast cancer are a consequence of metastatic disease. Thus, metastasis is a formidable and clearly an unmet challenge. We identified that NMI (N-Myc Interactor) protein is undetectable in more than 60% of primary breast tumors that had undergone metastatic dissemination. To recapitulate this clinical scenario, we generated a mammary specific-NMI knockout (Nmi-KO) mouse. In this model, we deciphered that loss of NMI allows for unrestrained signaling through the Wnt/β-catenin pathway and enables mesenchymal transition (EMT) of mammary tumors cells leading to increased metastasis. We found that NMI protein loss is observed predominantly in triple negative breast cancers (TNBC). TNBC is inherently highly invasive and metastatic and is recognized for aberrantly activated Wnt/β-catenin signaling. While investigating cellular adaptations of TNBC to low doses of a Wnt/β-catenin inhibitor, iCRT14, we observed that iCRT14 clearly decreased the number of nucleoli per TNBC cell. The nucleolus is the primary site of ribosomal RNAs (rRNA) synthesis and assembly with ribosomal proteins. It is a vital component in the ability of a cancer cell to meet the dynamic metabolic demands of tumor progression. Classical pathologic diagnosis of tumor tissue has revealed that nucleolar hypertrophy and increased nucleolar number are predictive and prognostic parameters of increased mortality. Our observations reveal that TNBCs show increased number of nucleoli per cell compared to non-TNBC specimens. Despite the importance of Wnt/β-catenin signaling, there is a clear gap in knowledge about the relevance of this pathway to nucleolar functions, specifically in TNBCs. We hypothesize that TNBCs are `addicted to' elevated ribosome biogenesis. Our proposed investigations are designed to test if inhibition of Wnt/β-catenin signaling will be an effective approach to disable ribosome biogenesis of TNBCs, specifically in those that lack NMI expression. While Wnt/β-catenin signaling has been one of the major factors driving TNBC metastases, therapeutic strategies are still evolving. Our research efforts will advance this field and unravel critical information that identifies the novel drug targets. Overall our efforts are congruent with the mission of the VA women's health initiative.

年轻的军事妇女中乳腺癌的发生率显着（高20％至40％）。 现役女性的乳腺癌事件率是平均事件的七倍 所有服务成员的其他15种癌症类型的速率。据估计由于乳房而导致的死亡中有90％ 癌症是转移性疾病的结果。那，转移是一种强大的，显然是未经满足的 挑战。我们确定NMI（N-MYC相互作用者）蛋白在超过60％的原发性中是无法检测到的 经历了转移性传播的乳腺肿瘤。为了概括这种临床情况，我们 产生了乳腺特异性NMI敲除（NMI-KO）小鼠。在此模型中，我们决定失去 NMI允许通过Wnt/β-catenin途径进行不受限制的信号传导，并实现间质 乳腺肿瘤细胞的过渡（EMT）导致转移增加。我们发现NMI蛋白损失 主要观察到三重负乳腺癌（TNBC）。 TNBC本质上是侵入性的， 转移性，并因异常激活的Wnt/β-catenin信号传导而被识别。同时研究细胞 TNBC对低剂量的Wnt/β-catenin抑制剂ICRT14的适应，我们观察到ICRT14清楚 每个TNBC细胞的核仁数量减少。 核仁是核糖体RNA（rRNA）合成的主要部位，并与核糖体组装 蛋白质。它是癌细胞满足动态代谢需求的能力的重要组成部分 肿瘤进展。肿瘤组织的经典病理诊断表明核肥大 核数的增加是死亡率增加的预测和预后参数。我们的 观察结果表明，与非TNBC相比，TNBC显示每个细胞的核仁数量增加 标本。尽管Wnt/β-catenin信号传导很重要，但了解该差距很明显 该途径与核仁函数的相关性，特别是在TNBC中。我们假设TNBC是 “沉迷于核糖体生物发生。我们提出的调查旨在测试抑制 Wnt/β-catenin信号传导将是禁用TNBC的核糖体生物发生的有效方法，特别是 在那些缺乏NMI表达的人中。 虽然Wnt/β-catenin信号传导一直是驱动TNBC转移的主要因素之一，但治疗 策略仍在发展。我们的研究工作将推进这一领域，并揭示关键信息 识别新型药物靶标。总的来说，我们的努力与VA妇女的任务一致 健康计划。