Cytoplasmic cyclin E is an early event for progression to invasive breast cancer

细胞质周期蛋白 E 是进展为浸润性乳腺癌的早期事件

• 批准号: 10113558
• 负责人: KHANDAN KEYOMARSI
• 金额: $ 39.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10113558
• 关键词: ATP Citrate (pro-S)-Lyase; Affect; Aromatase; Biological Markers; Biological Models; Biological Process; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Epithelial Cells; CCNE1 gene; CDK2 gene; Cancer Model; Carcinoma; Cell Cycle; Cell Cycle Progression; Cell model; Centrosome; Cessation of life; Clinical; Clinical Trials; Complex; Cytoplasm; DNA Damage; DNA Sequence Alteration; DNA biosynthesis; Development; Diagnosis; Disease; ERBB2 gene; Event; G2/M Transition; Genes; Genomic Instability; Goals; HBO1 histone acetyltransferase; Human; In Vitro; Indolent; Intervention; Knock-out; Laboratories; Lead; Length; Lesion; Letrozole; Leukocyte Elastase; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammalian Cell; Mammary Tumorigenesis; Mammary gland; Maps; Mediating; Mediator of activation protein; Metabolic Pathway; Modeling; Molecular Weight; Monitor; Mus; Mutation; Neoplastic Processes; Noninfiltrating Intraductal Carcinoma; Oncogenic; Outcome; Patient-Focused Outcomes; Patients; Pattern; Phase; Phase Transition; Phenotype; Prognostic Marker; Protein Isoforms; Protein Microarray Assay; Proteins; Recurrence; Regimen; Reporting; Research; Risk; Role; S Phase; Signal Transduction Alteration; Testing; Therapeutic; Transgenic Model; Up-Regulation; advanced breast cancer; aggressive therapy; breast cancer progression; cancer invasiveness; cancer type; clinically relevant; design; early detection biomarkers; experience; genetic regulatory protein; high risk; in vivo; in vivo Model; ineffective therapies; inhibitor/antagonist; malignant breast neoplasm; migration; neoplastic; novel; novel therapeutics; overexpression; preclinical study; programs; response; stem-like cell; targeted treatment; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumor growth; tumorigenesis

Project Summary Cyclin E, a key regulatory protein controlling the G1 to S phase transition in mammalian cells, is post- translationally modified by neutrophil elastase mediated proteolytic cleavage to generate the low molecular weight isoforms of cyclin E (LMW-E) that are detected in many cancer types. Our laboratory has elucidated several distinct oncological attributes of LMW-E versus full length cyclin E (EL) in breast cancer, using in vitro and in vivo model systems. In this application, using a robust inducible murine transgenic model of LMW-E mediated tumorigenesis, we have mapped some of the early events in the pre-neoplastic mammary gland that gives rise to aggressive tumors with high metastatic potential. These LMW-E oncogenic events permit the induction of sustained tumorigenesis even in the absence of LMW-E expression. These events include induction of DNA damage, upregulation of several genes involved in unregulated DNA replication and G2/M transition, and specific mutations in genes, such as ALK, that is readily targetable. These preliminary results have led to the following three testable hypotheses: (1) expression of LMW-E early in the pre-invasive breast cancer (i.e. ductal carcinoma in situ) results in induction of genomic alteration leading to an invasive carcinoma, (2) LMW-E in a cyclin E knockout model will result in a more aggressive phenotype than overexpression of EL, resulting in increased genomic instability, centrosome amplification and transformability in hMECs, (3) Inhibition of ALK, a secondary oncogenic event to LMW-E induction, early in the neoplastic process can inhibit tumorigenesis and also be used as a target for the treatment of triple negative breast cancers (TNBC) expressing LMW-E. The following aims are designed to test each aspect of these 3 hypotheses: Aim 1:Examine the role of cytoplasmic cyclin E in differentiating indolent versus high-risk ductal carcinoma in situ (DCIS). Aim 2: Investigate the mechanism of LMW-E mediated DNA damage response and centrosome amplification in the absence of endogenous cyclin E in somatic hMEC models. Aim 3: Investigate the role of ALK as a mediator of LMW-E mediated mammary tumorigenesis and as a therapeutic target in TNBC. These studies have the potential to identify LMW-E-induced early oncogenic events and provide the rationale to use LMW-E as a biomarker to identify the DCIS cases which are at high risk for developing invasive cancer. Our studies will show if ALK can be a viable target for the LMW-E overexpressing TNBC patients. Since there are already several ALK inhibitors, which have undergone Phase I-III clinical trials in malignancies other than breast, the translational of these pre-clinical studies to TNBC patients could occur readily.

项目概要 细胞周期蛋白 E 是哺乳动物细胞中控制 G1 至 S 期转变的关键调节蛋白。 通过中性粒细胞弹性蛋白酶介导的蛋白水解裂解进行翻译修饰，产生低分子 在许多癌症类型中检测到的细胞周期蛋白 E (LMW-E) 重量亚型。我们的实验室已阐明 使用体外实验，比较了乳腺癌中 LMW-E 与全长细胞周期蛋白 E (EL) 的几个不同的肿瘤学属性 和体内模型系统。在此应用中，使用 LMW-E 的稳健诱导型小鼠转基因模型 介导的肿瘤发生，我们绘制了肿瘤前乳腺中的一些早期事件， 产生具有高转移潜力的侵袭性肿瘤。这些 LMW-E 致癌事件允许 即使在没有 LMW-E 表达的情况下，也能诱导持续的肿瘤发生。这些事件包括 诱导 DNA 损伤，上调参与不受调控的 DNA 复制和 G2/M 的多个基因 转变，以及基因中的特定突变，例如 ALK，这些突变很容易被定位。这些初步结果 得出以下三个可检验的假设：（1）LMW-E在浸润前乳腺中早期表达 癌症（即原位导管癌）导致基因组改变的诱导，从而导致侵袭性 (2) 细胞周期蛋白 E 敲除模型中的 LMW-E 将导致比癌症更具侵袭性的表型 EL 过度表达，导致基因组不稳定性、中心体扩增和可转化性增加 在 hMEC 中，(3) 抑制 ALK，这是肿瘤早期 LMW-E 诱导的继发性致癌事件 该过程可以抑制肿瘤发生，也可以作为治疗三阴性乳腺的靶点 表达 LMW-E 的癌症 (TNBC)。以下目标旨在测试这 3 个方面的各个方面 假设：目标 1：检查细胞质细胞周期蛋白 E 在区分惰性导管和高危导管中的作用 原位癌（DCIS）。目标2：研究LMW-E介导的DNA损伤反应的机制和 在体细胞 hMEC 模型中，在缺乏内源性细胞周期蛋白 E 的情况下中心体扩增。目标 3：调查 ALK 作为 LMW-E 介导的乳腺肿瘤发生的介质以及作为治疗靶点的作用 TNBC。这些研究有可能识别 LMW-E 诱导的早期致癌事件，并提供 使用 LMW-E 作为生物标志物来识别具有高风险发展的 DCIS 病例的理由 侵袭性癌症。我们的研究将表明 ALK 是否可以成为 LMW-E 过表达 TNBC 的可行靶点 患者。由于目前已经有多种ALK抑制剂在中国进行I-III期临床试验 对于乳腺癌以外的恶性肿瘤，这些临床前研究可能会转化为 TNBC 患者 容易。