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: 10347166
• 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/10347166
• 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; 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 diagnosis; 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.

在年轻的女军人中，乳腺癌的发病率非常高（高出20%至40%）。 现役妇女乳腺癌发病率比平均发病率高7倍 在所有服役人员中，其他15种癌症的发病率。据估计，90%的乳腺癌死亡病例 癌症是转移性疾病的结果。因此，转移是一个可怕的，显然是一个未满足的 挑战.我们发现，NMI（N-Myc Interactor）蛋白在超过60%的原发性肝癌中检测不到。 已经转移扩散的乳腺肿瘤。为了概括这种临床情况，我们 产生乳腺特异性匪I敲除（Nmi-KO）小鼠。在这个模型中，我们破译了 NMI允许通过Wnt/β-连环蛋白途径进行不受限制的信号传导，并使间充质 乳腺肿瘤细胞的EMT导致转移增加。我们发现NMI蛋白的缺失 主要在三阴性乳腺癌（TNBC）中观察到。TNBC具有固有的高度侵入性， 转移性的并且被识别为异常激活的Wnt/β-连环蛋白信号传导。在研究细胞 TNBC对低剂量Wnt/β-连环蛋白抑制剂iCRT 14的适应，我们观察到iCRT 14清楚地 减少每个TNBC细胞的核仁数量。 核仁是核糖体RNA（rRNA）合成和与核糖体组装的主要场所。 proteins.它是癌细胞满足代谢动力学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学诊断显示， 核仁数目增加是死亡率增加的预测和预后参数。我们 观察结果显示，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信号转导的重要性，但关于Wnt/β-catenin信号转导的知识仍存在明显的空白。 该途径与核仁功能的相关性，特别是在TNBC中。我们假设， “沉迷于"核糖体生物合成的提高。我们提出的研究旨在测试是否抑制 Wnt/β-catenin信号通路将是阻断TNBC核糖体生物合成的有效途径， 在那些缺乏NMI表达的细胞中。 虽然Wnt/β-连环蛋白信号传导是驱动TNBC转移的主要因素之一，但治疗性TNBC转移是一个非常重要的因素。 战略仍在发展。我们的研究工作将推动这一领域的发展，并揭示关键信息， 确定新的药物靶点。总的来说，我们的努力与退伍军人事务部妇女的使命是一致的。 健康倡议。