Mechanism of chemoresistance mediated by TGF-beta
TGF-β介导的化疗耐药机制
基本信息
- 批准号:9324482
- 负责人:
- 金额:$ 32.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-05-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATM Signaling PathwayAccelerometerAnimalsApoptosisBindingBiological AssayBreast Cancer CellCancer PatientCell CycleCellsClinicalComplexDNADNA BindingDNA DamageDevelopmentDisease ProgressionDissectionDown-RegulationDoxycyclineDrug ControlsDrug resistanceExhibitsFutureGenesGenetic TranscriptionGoalsHumanInterventionLinkMADH2 geneMADH4 geneMSH2 geneMalignant NeoplasmsMediatingMediator of activation proteinMicroRNAsModelingMolecularMolecular ProfilingMolecular and Cellular BiologyMonitorMutateNormal CellOutcomePathway interactionsPatientsPharmaceutical PreparationsPhenotypePoly(ADP-ribose) PolymerasesProcessRNARNA BindingRegulationReporterReportingResistanceRoleSignal TransductionStagingTP53 geneTestingTherapeuticTransducersTransforming Growth Factor betaTransforming Growth Factor beta ReceptorsTransforming Growth FactorsTransplantationTreatment EfficacyTumor Suppressor Proteinscancer cellcancer therapychemotherapychromatin immunoprecipitationcofactorcytokinedrug efficacyexperiencein vitro Assayin vivoinducible gene expressioninhibitor/antagonistinnovationinsightknock-downmalignant breast neoplasmneoplastic cellnew therapeutic targetnovelnovel strategiesnovel therapeuticsoutcome forecastoverexpressionp53-binding protein 1responsesensortargeted treatmenttherapy resistanttranscription factortriple-negative invasive breast carcinomatumortumor growthtumor xenograftvector
项目摘要
DESCRIPTION (provided by applicant): Many chemotherapy drugs act against cancer cells by causing damage to the DNA. Resistance to chemotherapy is a major clinical obstacle in cancer treatment. The mechanisms of chemoresistance in cancer patients are not fully understood, leading to urgent needs for determining factors that control drug response and developing novel therapies to enhance the treatment efficacy. Signaling from transforming growth factor (TGF) ß, a tumor suppressor in normal cells, is hijacked in cancer to promote disease progression. In breast cancer, TGF-ß is linked to poor clinical outcomes and chemoresistance through mechanisms that remain largely unknown. Our previous studies indicate that in breast cancer cells, TGF-ß induces microRNAs (miR-21 and miR-181) that target the DNA damage sensors ATM and MSH2, and may therefore regulate cancer response to genotoxic chemotherapy. The goals of this study are to dissect the molecular mechanism of
TGF-ß-mediated chemoresistance, and to explore potential therapies to enhance drug efficacy. In Aim 1, TGF-ß action on cell response to various DNA-damaging treatments and to inhibition of poly(ADP-ribose) polymerase (PARP) will be determined in breast cancer cells with different p53 status using established molecular and cellular biology assays. The role of the
TGF-ß-regulated miRNAs and the ATM/MSH2 pathways will be determined using gene knockdown and overexpression strategies. In Aim 2, the hypothesis that enhanced SMAD2/3 binding to their RNA targets mediates TGF-ß's functional shift in cancer cells towards inducing miRNA regulation and chemoresistance will be examined. Breast cancer cells expressing various levels of the SMAD2/3 cofactors (i.e., SMAD4, Drosha and p68) will be examined for their dynamic regulation of SMAD2/3 function and TGF-ß effect. In Aim 3, the effect of TGF-ß on chemotherapy response and the mechanism identified in the first two aims will be evaluated in animal tumor models. Novel strategies to therapeutically suppress this TGF-ß function and enhance the treatment efficacy will be explored. This study will enable better understandings of drug resistance and of TGF-ß signaling as both a marker and a target in cancer treatment. Although the mechanism identified herein may have a general application to understanding cancer and defining treatments, our study has added significance for clinically aggressive, hard-to-treat basal- like (mainly triple-negative) breast cancer that often experience active TGF-ß signaling. This study will provide novel insight into the functional switch of TGF-ß in cancer via SMAD2/3-mediated miRNA processing. Understanding TGF-ß-mediated chemoresistance may reveal novel therapeutic targets and strategies that will enhance the chemotherapy efficacy for cancers that lack targets for systemic treatments. Our long-term objectives are to validate this mechanism in primary cancers and establish standard approaches to identify patients suitable for therapies targeting TGF-ß's drug resistant effect, and to understand the global effect of TGF-ß -mediated miRNA dysregulation in human cancer.
描述(由适用提供):许多化学疗法药物通过损害DNA来对癌细胞起作用。对化学疗法的抗性是癌症治疗中的主要临床障碍。癌症患者化学耐药性的机制尚未完全了解,从而迫切需要确定控制药物反应并开发新疗法以提高治疗效率的因素。在正常细胞中抑制肿瘤的转化生长因子(TGF)的信号传导被劫持在癌症中以促进疾病进展。在乳腺癌中,TGF-ß通过仍然未知的机制与临床结局不良和化学抗性有关。我们先前的研究表明,在乳腺癌细胞中,TGF-β诱导靶向DNA损伤传感器ATM和MSH2的microRNA(miR-21和miR-181),因此可能调节癌症对遗传毒性化学疗法的反应。这项研究的目标是剖析分子机制
TGF-β介导的化学抗性,并探索潜在的疗法以提高药物效率。在AIM 1中,将使用已建立的分子和细胞生物学测定法在不同的p53状态的乳腺癌细胞中确定TGF-β对各种DNA损害治疗的细胞反应和抑制聚(ADP-核糖)聚合酶(PARP)的作用。角色
TGF-ß调节的miRNA和ATM/MSH2途径将使用基因敲低和过表达策略确定。在AIM 2中,将研究介导TGF-ß在癌细胞中介导TGF-ß对诱导miRNA调节和化学抗性的介导的smad2/3结合的假设。将检查表达各种水平的SMAD2/3辅因子(即Smad4,Drosha和P68)的乳腺癌细胞,以动态调节SMAD2/3功能和TGF-ß效应。在AIM 3中,将在动物肿瘤模型中评估TGF-β对化学疗法反应和前两个目标中确定的机制的影响。将探索热抑制此TGF-ß功能并提高治疗效率的新型策略。这项研究将使人们能够更好地理解耐药性和TGF-ß信号传导,这既是癌症治疗的标志物,又是目标。尽管此处确定的机制可能具有了解癌症和定义治疗的一般应用,但我们的研究对临床侵略性,难以治疗的基本样(主要是三阴性)乳腺癌的意义增加了,通常会经历主动的TGF-ß信号传导。这项研究将通过SMAD2/3-介导的miRNA加工来提供对TGF-ß在癌症中功能转换的新见解。了解TGF-β介导的化学耐药性可能会揭示出新的治疗靶标和策略,从而增强缺乏全身治疗靶标的癌症的化学疗法有效性。我们的长期目标是在初级癌症中验证这种机制,并建立标准方法,以鉴定适合针对TGF-β耐药作用的疗法的患者,并了解TGF-β介导的miRNA在人类癌症中的全球效应。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cancer-derived extracellular vesicles: the 'soil conditioner' in breast cancer metastasis?
- DOI:10.1007/s10555-016-9639-8
- 发表时间:2016-12
- 期刊:
- 影响因子:0
- 作者:Chin AR;Wang SE
- 通讯作者:Wang SE
Cancer Tills the Premetastatic Field: Mechanistic Basis and Clinical Implications.
- DOI:10.1158/1078-0432.ccr-16-0028
- 发表时间:2016-08-01
- 期刊:
- 影响因子:0
- 作者:Chin AR;Wang SE
- 通讯作者:Wang SE
Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis.
- DOI:10.1016/j.ccr.2014.03.007
- 发表时间:2014-04-14
- 期刊:
- 影响因子:50.3
- 作者:Zhou W;Fong MY;Min Y;Somlo G;Liu L;Palomares MR;Yu Y;Chow A;O'Connor ST;Chin AR;Yen Y;Wang Y;Marcusson EG;Chu P;Wu J;Wu X;Li AX;Li Z;Gao H;Ren X;Boldin MP;Lin PC;Wang SE
- 通讯作者:Wang SE
Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-κB.
- DOI:10.1038/srep05750
- 发表时间:2014-07-18
- 期刊:
- 影响因子:4.6
- 作者:Chow A;Zhou W;Liu L;Fong MY;Champer J;Van Haute D;Chin AR;Ren X;Gugiu BG;Meng Z;Huang W;Ngo V;Kortylewski M;Wang SE
- 通讯作者:Wang SE
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Shizhen Emily Wang其他文献
Microenvironment and Immunology CCL 2 Mediates Crosstalk betweenCancer Cells and Stromal Fibroblasts That Regulates Breast Cancer Stem Cells
微环境和免疫学 CCL 2 介导癌细胞和基质成纤维细胞之间的串扰,从而调节乳腺癌干细胞
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
Akihiro Tsuyada;A. Chow;Jun Wu;G. Somlo;P. Chu;So;A. Loera;T. Luu;A. Li;Xiwei Wu;W. Ye;Shiuan Chen;Weiying Zhou;Yang Yu;Yuan;X. Ren;Hui Li;P. Scherle;Y. Kuroki;Shizhen Emily Wang - 通讯作者:
Shizhen Emily Wang
Extracellular Vesicles and Metastasis.
- DOI:
10.1101/cshperspect.a037275 - 发表时间:
2020-07 - 期刊:
- 影响因子:5.4
- 作者:
Shizhen Emily Wang - 通讯作者:
Shizhen Emily Wang
MicroRNA Let-7 in B lymphocyte activation
MicroRNA Let-7 在 B 淋巴细胞激活中的作用
- DOI:
10.18632/aging.101968 - 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Shuai Jiang;Wei Yan;Shizhen Emily Wang - 通讯作者:
Shizhen Emily Wang
Shizhen Emily Wang的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Shizhen Emily Wang', 18)}}的其他基金
Role of breast cancer secreted miRNA in brain metastasis
乳腺癌分泌的miRNA在脑转移中的作用
- 批准号:
10342786 - 财政年份:2022
- 资助金额:
$ 32.16万 - 项目类别:
Role of breast cancer secreted miRNA in brain metastasis
乳腺癌分泌的miRNA在脑转移中的作用
- 批准号:
10584489 - 财政年份:2022
- 资助金额:
$ 32.16万 - 项目类别:
Role of breast cancer-secreted miRNA in directing a stromal metabolic plasticity
乳腺癌分泌的 miRNA 在指导基质代谢可塑性中的作用
- 批准号:
10221635 - 财政年份:2017
- 资助金额:
$ 32.16万 - 项目类别:
Targeting Chemotherapy-induced Breast Cancer Stemness
针对化疗引起的乳腺癌干细胞
- 批准号:
10227677 - 财政年份:2017
- 资助金额:
$ 32.16万 - 项目类别:
Mechanism of chemoresistance mediated by TGF-beta
TGF-β介导的化疗耐药机制
- 批准号:
8826058 - 财政年份:2012
- 资助金额:
$ 32.16万 - 项目类别:
Role of miR-105 in breast cancer metastasis
miR-105在乳腺癌转移中的作用
- 批准号:
8538323 - 财政年份:2012
- 资助金额:
$ 32.16万 - 项目类别:
Mechanism of chemoresistance mediated by TGF-beta
TGF-β介导的化疗耐药机制
- 批准号:
8217621 - 财政年份:2012
- 资助金额:
$ 32.16万 - 项目类别:
Mechanism of chemoresistance mediated by TGF-beta
TGF-β介导的化疗耐药机制
- 批准号:
8463147 - 财政年份:2012
- 资助金额:
$ 32.16万 - 项目类别:
Role of miR-105 in breast cancer metastasis
miR-105在乳腺癌转移中的作用
- 批准号:
8394989 - 财政年份:2012
- 资助金额:
$ 32.16万 - 项目类别:
Mechanism of chemoresistance mediated by TGF-beta
TGF-β介导的化疗耐药机制
- 批准号:
8639967 - 财政年份:2012
- 资助金额:
$ 32.16万 - 项目类别:
相似国自然基金
基于腔光机械效应的石墨烯光纤加速度计研究
- 批准号:62305039
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于自持相干放大的高精度微腔光力加速度计研究
- 批准号:52305621
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
面向结构和地震运动监测的低成本GNSS和加速度计集成方法研究
- 批准号:42311530062
- 批准年份:2023
- 资助金额:10 万元
- 项目类别:国际(地区)合作与交流项目
绝缘体辐射诱导电荷致工作态三明治式MEMS加速度计敏感结构非单向性损伤机制研究
- 批准号:12305313
- 批准年份:2023
- 资助金额:30.00 万元
- 项目类别:青年科学基金项目
柔性MEMS谐振式加速度计的共形设计与热弹性耦合动力学分析
- 批准号:12202240
- 批准年份:2022
- 资助金额:30.00 万元
- 项目类别:青年科学基金项目
相似海外基金
Interstitial pressure sensor to detect fluid status
间隙压力传感器检测液体状态
- 批准号:
10603623 - 财政年份:2023
- 资助金额:
$ 32.16万 - 项目类别:
Characterizing Acute Exercise Response in Restrictive Eating Disorders
限制性饮食失调的急性运动反应特征
- 批准号:
10739107 - 财政年份:2023
- 资助金额:
$ 32.16万 - 项目类别:
Timing of Physical Activity on Cardiometabolic Health Outcomes
体力活动时间对心脏代谢健康结果的影响
- 批准号:
10877418 - 财政年份:2023
- 资助金额:
$ 32.16万 - 项目类别:
GPLD1: Association with Cognition and Amelioration through Exercise in Aging People with HIV
GPLD1:老年艾滋病毒感染者通过运动与认知和改善的关系
- 批准号:
10403225 - 财政年份:2022
- 资助金额:
$ 32.16万 - 项目类别:
A health-literacy module for overweight adolescents and their parents on canine physical activity, nutrition and behavior: Enhancing DHHS'BodyWorks program at a Federally Qualified Health Center
为超重青少年及其父母提供有关犬类身体活动、营养和行为的健康素养模块:在联邦合格健康中心加强 DHHS 的 BodyWorks 计划
- 批准号:
10579776 - 财政年份:2022
- 资助金额:
$ 32.16万 - 项目类别: