Cytoplasmic cyclin E is an early event for progression to invasive breast cancer
Cytoplasmic cyclin E is an early event for progression to invasive breast cancer
批准号:
10550153
负责人:
KHANDAN KEYOMARSI
金额:
$38.62万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
未结题
起止时间:
2018-02-01 至 2025-01-31
关键词:
ATP Citrate (pro-S)-LyaseAffectAromataseBiological MarkersBiological ModelsBiological ProcessBreastBreast Cancer CellBreast Cancer PatientBreast Cancer TreatmentBreast Epithelial CellsCCNE1 geneCDK2 geneCarcinomaCell CycleCell Cycle ProgressionCell modelCentrosomeCessation of lifeClinicalClinical TrialsComplexCytoplasmDNA DamageDNA Sequence AlterationDNA biosynthesisDevelopmentDiagnosisDiseaseERBB2 geneEventG2/M TransitionGenesGenomic InstabilityGoalsHBO1 histone acetyltransferaseHumanIn VitroIndolentInterventionInvadedKnock-outLaboratoriesLengthLesionLetrozoleLeukocyte ElastaseLinkMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of urinary bladderMammalian CellMammary TumorigenesisMammary glandMapsMediatingMediatorMetabolic PathwayModelingMolecular WeightMonitorMusMutationNeoplastic ProcessesNoninfiltrating Intraductal CarcinomaOncogenicOncologyOutcomePatient-Focused OutcomesPatientsPatternPhasePhase TransitionPhenotypePrognostic MarkerProtein IsoformsProtein Microarray AssayProteinsRecurrenceRegimenReportingResearchRiskRoleS phaseSignal Transduction AlterationTestingTherapeuticTransgenic ModelUp-Regulationadvanced breast canceraggressive therapybreast cancer progressioncancer invasivenesscancer typeclinically relevantdesignearly detection biomarkersexperiencegenetic regulatory proteinhigh riskin vivoin vivo Modelineffective therapiesinhibitormalignant breast neoplasmmigrationneoplasticnovelnovel therapeuticsoverexpressionpreclinical studyprogramsresponsestem-like celltargeted treatmenttherapeutic targettriple-negative invasive breast carcinomatumortumor growthtumorigenesis
中文摘要
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。
英文摘要
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.
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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
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
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
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
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
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海外基金