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: 10550153
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550153
• 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; 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; Invaded; Knock-out; Laboratories; Length; Lesion; Letrozole; Leukocyte Elastase; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammalian Cell; Mammary Tumorigenesis; Mammary gland; Maps; Mediating; Mediator; Metabolic Pathway; Modeling; Molecular Weight; Monitor; Mus; Mutation; Neoplastic Processes; Noninfiltrating Intraductal Carcinoma; Oncogenic; Oncology; 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是控制哺乳动物细胞从G1期向S期转变的关键调控蛋白，是细胞周期调控的后调控蛋白。 中性粒细胞弹性蛋白酶介导的蛋白水解酶的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)的重量异构体。我们的实验室已经澄清了 LMW-E与全长细胞周期蛋白E(EL)在乳腺癌中的几个不同的肿瘤学特性 和活体模型系统。在这个应用中，使用了一种健壮的可诱导的小鼠LMW-E转基因模型 介导性肿瘤发生，我们已经绘制了一些肿瘤前乳腺的早期事件图 会导致具有高转移潜能的侵袭性肿瘤。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。这些活动包括 诱导DNA损伤，上调参与非调控DNA复制的几个基因和G2/M 过渡，以及基因的特定突变，如ALK，很容易被靶向。这些初步结果 导致了以下三个可检验的假说：(1)LMW-E在早期侵袭前乳腺中的表达 癌症(即导管原位癌)导致基因组改变，导致浸润性病变。 癌，(2)Cyclin E基因敲除模型中的LMW-E将导致比 EL的过度表达，导致基因组的不稳定性、中心体扩增和转化性增加 在hMEC中，(3)抑制ALK，这是LMW-E诱导的一种继发性致癌事件，在肿瘤早期 Process可以抑制肿瘤的形成，也可以作为治疗三阴性乳腺的靶点 肿瘤细胞(TNBC)表达LMW-E。以下目标旨在测试这3个方面的各个方面 假设：目标1：检测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)。目的：探讨LMW-E介导的DNA损伤反应及机制。 在体细胞hMEC模型中缺乏内源性细胞周期蛋白E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导物和治疗靶点的作用 TNBC。这些研究有可能识别LMW-E诱导的早期致癌事件，并提供 用LMW-E作为生物标志物识别高危DCIS的理论基础 浸润性癌症。我们的研究将显示ALK是否可以成为过度表达TNBC的LMW-E的可行靶点 病人。由于已经有几种ALK抑制剂，它们已经在#年进行了I-III期临床试验 乳腺以外的恶性肿瘤，这些临床前研究的翻译可能发生在TNBC患者身上 很容易。

项目成果

Targeting Replicative Stress and DNA Repair by Combining PARP and Wee1 Kinase Inhibitors Is Synergistic in Triple Negative Breast Cancers with Cyclin E or BRCA1 Alteration.

• DOI: 10.3390/cancers13071656
• 发表时间: 2021-04-01
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Chen X;Yang D;Carey JPW;Karakas C;Albarracin C;Sahin AA;Arun BK;Guray Durak M;Li M;Kohansal M;Bui TN;Ha MJ;Hunt KK;Keyomarsi K
• 通讯作者: Keyomarsi K

LMW cyclin E and its novel catalytic partner CDK5 are therapeutic targets and prognostic biomarkers in salivary gland cancers.

• DOI: 10.1038/s41389-021-00324-z
• 发表时间: 2021-05-14
• 期刊: Oncogenesis
• 影响因子: 6.2
• 作者: Lulla AR;Akli S;Karakas C;Ha MJ;Fowlkes NW;Mitani Y;Bui T;Wang J;Rao X;Hunt KK;Meijer L;El-Naggar AK;Keyomarsi K
• 通讯作者: Keyomarsi K

PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers.

• DOI: 10.1080/13543784.2022.2067527
• 发表时间: 2022-06
• 期刊: EXPERT OPINION ON INVESTIGATIONAL DRUGS
• 影响因子: 6.1
• 作者: Luo, Linjie;Keyomarsi, Khandan
• 通讯作者: Keyomarsi, Khandan

Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies.

• DOI: 10.1158/0008-5472.can-18-1235
• 发表时间: 2018-10-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Caruso JA;Duong MT;Carey JPW;Hunt KK;Keyomarsi K
• 通讯作者: Keyomarsi K

Low-molecular-weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer.

• DOI: 10.1038/s41388-022-02527-z
• 发表时间: 2022-12
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Li, Mi;Tsavachidis, Spiridon;Wang, Fuchenchu;Bui, Tuyen;Tuyen Duong Thanh Nguyen;Luo, Linjie;Multani, Asha S.;Bondy, Melissa L.;Hunt, Kelly K.;Keyomarsi, Khandan
• 通讯作者: Keyomarsi, Khandan