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: 10337331
• 负责人: KHANDAN KEYOMARSI
• 金额: $ 38.62万
• 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/10337331
• 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; 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.

项目摘要 细胞周期蛋白E是哺乳动物细胞中控制G1期向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切割进行修饰，以产生低分子量的 在许多癌症类型中检测到的细胞周期蛋白E（LMW-E）的重量亚型。我们的实验室已经阐明了 乳腺癌中LMW-E与全长细胞周期蛋白E（EL）的几种不同的肿瘤学属性， 和体内模型系统。在本申请中，使用LMW-E的稳健的诱导型鼠转基因模型， 介导的肿瘤发生，我们已经绘制了肿瘤前乳腺的一些早期事件， 引起具有高转移潜力的侵袭性肿瘤。这些LMW-E致癌事件允许 诱导持续的肿瘤发生，即使在LMW-E表达的情况下。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的几个基因 转换和基因中的特定突变，如ALK，这是很容易靶向的。这些初步结果 已经导致了以下三个可检验的假设：（1）LMW-E在浸润前乳腺的早期表达 癌症（即原位导管癌）导致基因组改变的诱导，从而导致侵袭性肿瘤。 （2）LMW-E在细胞周期蛋白E敲除模型中将导致比在细胞周期蛋白E敲除模型中更侵袭性的表型。 EL的过度表达，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）在肿瘤形成早期，ALK抑制，这是LMW-E诱导的继发性致癌事件， 该过程可以抑制肿瘤发生，也可以用作治疗三阴性乳腺癌的靶点。 表达LMW-E的癌症（TNBC）。以下目标旨在测试这3个方面的每个方面 假设：目的1：检测细胞质细胞周期蛋白E在鉴别惰性导管与高危导管中的作用。 原位癌（DCIS）。目的2：探讨LMW-E介导DNA损伤反应的机制， 在体细胞hMEC模型中内源性细胞周期蛋白E不存在下的中心体扩增。目标3：调查 ALK作为LMW-E介导的乳腺肿瘤发生的介质和作为治疗靶点在 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发生DCIS的高风险病例的依据 侵袭性癌症我们的研究将显示ALK是否可以成为LMW-E过表达TNBC的可行靶点。 患者由于已经有几种ALK抑制剂，它们已经经历了I-III期临床试验， 乳腺以外的恶性肿瘤，可能会将这些临床前研究转化为TNBC患者 很容易。