Mechanisms that impact metastatic progression of triple negative breast cancer

年轻的女军人患乳腺癌的几率很高(高出20%到40%)。 在职女性的乳腺癌发病率是平均发病率的7倍 在所有服役人员中，15种其他癌症类型的比率。据估计，90%的死亡是由于乳房 癌症是转移性疾病的结果。因此，转移是一个令人敬畏的，显然是一个未得到满足的 挑战。我们发现，在超过60%的原发肿瘤中未检测到N-Myc相互作用蛋白 已发生转移扩散的乳腺肿瘤。概括一下这一临床场景，我们 产生了一只乳腺特异的NMI基因敲除(NMI-KO)小鼠。在这个模型中，我们破译了 Nmi允许通过Wnt/β-Catenin途径无限制地传递信号，并使间充质 乳腺肿瘤细胞的转化(EMT)导致转移增加。我们发现NMI蛋白丢失 主要见于三阴性乳腺癌(TNBC)。TNBC本身就具有高度侵袭性 转移性，并被认为是异常激活的Wnt/β-catenin信号。在调查移动电话时 TnBC对低剂量Wnt/β-连环蛋白抑制剂iCRT14的适应，我们观察到iCRT14 减少每个TNBC细胞的核仁数目。 核仁是核糖体RNA(RRNA)合成和与核糖体组装的主要部位 蛋白质。它是癌细胞满足动态代谢需求能力的重要组成部分。 肿瘤进展。肿瘤组织的经典病理诊断显示核仁肥大。 核仁数目增加是死亡率增加的预测和预后参数。我们的 观察表明，与非TNBC相比，TNBCs的每个细胞的核仁数量增加 标本。尽管WNT/β-连环蛋白信号转导很重要，但对WNT/WNT-连环蛋白信号转导途径的认识还存在明显的空白 这一途径与核仁功能的相关性，特别是在TNBCs中。我们假设TNBCs是 “沉迷于”核糖体生物发生。我们提议的调查旨在测试是否抑制了 Wnt/β-Catenin信号转导系统将成为抑制TNBCs核糖体生物发生的有效途径 在那些缺乏NMI表达的人中。 虽然Wnt/β-catenin信号转导是导致肿瘤转移的主要因素之一，但治疗性 战略仍在发展中。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。总体而言，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。

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.