Investigating How a Balance of Negative and Positive ETS Factors Controls Prostate Oncogenesis
研究负性和正性 ETS 因素的平衡如何控制前列腺肿瘤发生
基本信息
- 批准号:10229585
- 负责人:
- 金额:$ 26.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAndrogen ReceptorAndrogensAutomobile DrivingBindingBinding SitesBioinformaticsCancer BiologyCancer EtiologyCancer PatientCancerousCellsChIP-seqChromatinClinicalConsensusDNA BindingDataDependenceDetectionDevelopmentDiseaseERG geneETV1 geneETV3 geneETV6 geneEnvironmentEquilibriumEventFundingGene FusionGenesGeneticGenetic TranscriptionGenitourinary systemGenomicsGrowthHumanInternationalInvestigationLaboratoriesLeadLightMalignant NeoplasmsMalignant neoplasm of prostateManuscriptsMapsMass Spectrum AnalysisMediatingMedical OncologyMemorial Sloan-Kettering Cancer CenterMentorsMentorshipModelingMolecularMorphologyMusMutationNatureOncogenicOrganoidsOutputPTEN genePathogenesisPhenotypePhysiciansPoint MutationPositioning AttributeProstateProstatic NeoplasmsProtein FamilyProteinsReceptor SignalingRecurrenceReportingResearchResearch PersonnelRoleScientistServicesSiteTMPRSS2 geneTestingTestosteroneTrainingTumor Suppressor ProteinsWorkbasecareercareer developmentcell growthclinical biomarkersexperienceinstructorknock-downleukemialoss of function mutationmouse modeloverexpressionprogramsprostate cancer cellreceptorsarcomatargeted treatmenttherapy developmenttranscription factortumortumor growthtumorigenesis
项目摘要
Preliminary Data: Half of all prostate cancers are caused by a gene-fusion that enables androgens to drive
expression of the normally silent ETS transcription factor ERG in prostate cells. Recent genomic landscape
studies of such cancers have reported rare but recurrent point mutations and narrow focal deletions in the ETS
repressor ERF. Here we show these ERF mutations cause decreased protein stability and are mostly
exclusive from those with ERG fusions. ERF loss recapitulates the morphologic and phenotypic features of
ERG gain in normal mouse prostate cells, including expansion of the androgen receptor (AR) transcriptional
repertoire, and ERF has tumor suppressor activity in the same genetic background of PTEN loss that yields
oncogenic activity by ERG. In the more common situation of a tumor possessing wild-type ERF, ChIP-seq
studies indicate that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites in both normal and
cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent
tumor growth and ERF loss rescues ERG-positive prostate cancer cells from ERG dependency. This
preliminary data is described in the applicant's first author manuscript in press at Nature. Rationale and
Aims: We have now discovered that loss of function mutations and copy number deletions in `negative' ETS
factors are commonplace in prostate cancer. I) We aim to determine the collective importance of negative
ETS factor (ETV3 and ETV6) mutations in prostate cancer. II) We aim to determine whether ERF negative
regulates AR by affecting AR's ability to bind DNA or by actively repressing its function. III) We believe that
negative ETS factors are continually outcompeting positive ETS factors, even in normal prostate. We seek to
identify these endogenous positive ETS factors. Impact: The results of these studies will describe how ETS
factors coordinate within normal prostate cells. They may also shed light on why TMPRSS2-ERG is a poor
clinical biomarker. Thirdly, they may explain the pathogenesis of the half of prostate cancers that lack
TMPRSS2-ERG. And finally, they may shed light on the oncogenesis of other ETS-dependent cancers such
as leukemias and sarcomas. Applicant and career development: The applicant, Dr. Rohit Bose, is
performing his postdoctoral work in Charles Sawyers laboratory and is also an Instructor in the Genitourinary
Service at Memorial Sloan Kettering Cancer Center (MSKCC). He has outlined a 5-year career plan that
builds upon his research background studying molecular mechanisms of prostate oncogenesis and his clinical
training in medical oncology. Dr. Bose will conduct the proposed research under the mentorship of Dr. Charles
Sawyers, an internationally recognized expert in prostate cancer biology and targeted therapy development,
with a strong track record of training successful physician scientists. MSKCC provides the ideal institutional
environment for Dr. Bose to embark on the proposed research program and transition to a position as an
independent academic investigator with his own laboratory and R01 funding.
初步数据:一半的前列腺癌是由雄激素驱动的基因融合引起的
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Rohit Bose其他文献
Rohit Bose的其他文献
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{{ truncateString('Rohit Bose', 18)}}的其他基金
Simulating Ancestrally Unbiased Tumor Evolution To Interrogate Drug Resistance
模拟祖先无偏见的肿瘤进化来询问耐药性
- 批准号:
10687776 - 财政年份:2023
- 资助金额:
$ 26.03万 - 项目类别:
Investigating How a Balance of Negative and Positive ETS Factors Controls Prostate Oncogenesis
研究负性和正性 ETS 因素的平衡如何控制前列腺肿瘤发生
- 批准号:
10471816 - 财政年份:2018
- 资助金额:
$ 26.03万 - 项目类别:
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