The roles of TRIM24 in breast cancer
TRIM24 在乳腺癌中的作用
基本信息
- 批准号:10117196
- 负责人:
- 金额:$ 40.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-03-01 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAmino Acid MotifsApoptosisBiologicalBiological ModelsBreastBreast Cancer ModelBreast Cancer PatientBreast CarcinomaBreast Epithelial CellsBromodomainCell LineCellsCessation of lifeChoristomaChromatinClustered Regularly Interspaced Short Palindromic RepeatsCohort StudiesCultured CellsCytometryDataData SetDevelopmentDiseaseEpigenetic ProcessEstrogen ReceptorsEstrogensExcisionGene ExpressionGenetic TranscriptionGoalsGrowthHistonesHumanImageImpairmentIn VitroKnowledgeLaboratoriesMCF7 cellMalignant NeoplasmsMammary NeoplasmsMammary TumorigenesisMediatingMetabolismModelingMolecularMolecular AnalysisMolecular ProfilingMusMutagenesisMutateMutationNuclear ReceptorsOncogenicOutcomePathway interactionsPatient-derived xenograft models of breast cancerPatientsPhenotypePhysiologicalPost-Translational Protein ProcessingProcessProteinsReaderReadingRecurrenceRegulationRoleSmall Interfering RNASpecificityTP53 geneTRIM MotifTestingThe Cancer Genome AtlasTherapeuticTransgenesTumor stageTumor-DerivedUbiquitinationWorkbasebreast tumorigenesisc-myc Genescancer subtypescarcinogenesischromatin immunoprecipitationcohortembryonic stem cellgenetic regulatory proteinhistone modificationinhibitor/antagonistinnovationmalignant breast neoplasmmammarymammary epitheliummouse modeloverexpressionpatient derived xenograft modelrecruitsmall molecule inhibitortherapeutic targettranscriptome sequencingtumortumor initiationtumor progressiontumorigenesisubiquitin-protein ligase
项目摘要
PROJECT SUMMARY
Breast cancer is a deadly disease and new strategies are needed to fulfill the goals of treatment and
eradication. Recent development of epigenetic-based inhibitors offers new avenues of potential therapeutics
for breast and other human cancers. Our work using a new mouse model of breast cancer that parallels the
aberrant expression of TRIM24 in all breast cancer sub-types will be used to gain a deeper understanding of
tumor development and treatment. Epigenetic regulators are frequent targets of aberrant regulation,
amplification or mutation in all human cancers. Histone “writers”, “erasers” and “readers” are epigenetic
regulators that catalyze addition, removal and/or interaction, respectively, with post-translational modifications
(PTMs) of histones or other modified proteins, with subsequent regulatory outcomes for gene expression. Our
laboratory discovered Tripartite Motif Protein 24 (TRIM24) as a histone reader and showed that TRIM24: (i)
ubiquitinated p53 and siRNA-depletion of TRIM24 led to p53-dependent apoptosis of embryonic stem cells and
breast cancer-derived cells (MCF7), (ii) recruited estrogen receptor to chromatin by PHD/bromodomain reading
of a unique signature of histone PTMs (H3K4me0; H3K23ac) to co-regulate estrogen-dependent transcription,
(iii) induced transformation of immortalized human mammary epithelial cells (iHMECs) by altering metabolism
and up-regulating c-Myc expression when ectopically expressed, and (iv) a small molecule inhibitor of the
TRIM24 bromodomain disrupts chromatin interactions in vitro. Importantly, we found that aberrant expression
of TRIM24 negatively correlates with breast cancer patient survival. TRIM24 is over expressed in all sub-types
of breast cancer and is highest in basal breast cancers. We developed a mouse model of TRIM24-expressing
breast cancers by conditional over-expression of a Trim24 transgene in mammary epithelia. We saw that
aberrant, tissue-specific expression of TRIM24 is sufficient for tumor initiation, development and progression to
highly heterogeneous mammary carcinomas. We hypothesize that our proposed, multi-faceted studies,
including mouse models, cultured cells and in vitro analyses will uncover how aberrant expression of TRIM24
drives heterogeneous tumor development in mammary/breast epithelia, and that our findings will further
development of epigenetic-based therapeutics to treat breast cancers. Our long-term goal is to leverage a
deep mechanistic understanding of TRIM24 functions toward innovative therapeutic approaches to treat breast
and other cancers in humans.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
HDAC6: A Key Link Between Mitochondria and Development of Peripheral Neuropathy.
- DOI:10.3389/fnmol.2021.684714
- 发表时间:2021
- 期刊:
- 影响因子:4.8
- 作者:English K;Barton MC
- 通讯作者:Barton MC
Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer.
- DOI:10.1038/s41467-021-25650-z
- 发表时间:2021-09-10
- 期刊:
- 影响因子:16.6
- 作者:Shah VV;Duncan AD;Jiang S;Stratton SA;Allton KL;Yam C;Jain A;Krause PM;Lu Y;Cai S;Tu Y;Zhou X;Zhang X;Jiang Y;Carroll CL;Kang Z;Liu B;Shen J;Gagea M;Manu SM;Huo L;Gilcrease M;Powell RT;Guo L;Stephan C;Davies PJ;Parker-Thornburg J;Lozano G;Behringer RR;Piwnica-Worms H;Chang JT;Moulder SL;Barton MC
- 通讯作者:Barton MC
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GUILLERMINA LOZANO其他文献
GUILLERMINA LOZANO的其他文献
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{{ truncateString('GUILLERMINA LOZANO', 18)}}的其他基金
Role of p53 Missense Mutations on Tumorigenesis in Vivo
p53 错义突变在体内肿瘤发生中的作用
- 批准号:
10097999 - 财政年份:2020
- 资助金额:
$ 40.2万 - 项目类别:
Role of p53 Missense Mutations on Tumorigenesis in Vivo
p53 错义突变在体内肿瘤发生中的作用
- 批准号:
10549823 - 财政年份:2020
- 资助金额:
$ 40.2万 - 项目类别:
Role of p53 Missense Mutations on Tumorigenesis in Vivo
p53 错义突变在体内肿瘤发生中的作用
- 批准号:
9883907 - 财政年份:2020
- 资助金额:
$ 40.2万 - 项目类别:
(PQ4) Mutations in the histone chaperone DAXX drive pancreatic neuroendocrine tumors not ductal adenocarcinomas
(PQ4) 组蛋白伴侣 DAXX 突变导致胰腺神经内分泌肿瘤而非导管腺癌
- 批准号:
9171873 - 财政年份:2016
- 资助金额:
$ 40.2万 - 项目类别:
CORE--MUTATION DETECTION & CHARACTERIZATION OF TUMOR SUPPRESSOR GENES
核心——突变检测
- 批准号:
6357989 - 财政年份:2000
- 资助金额:
$ 40.2万 - 项目类别:
CORE--MUTATION DETECTION & CHARACTERIZATION OF TUMOR SUPPRESSOR GENES
核心——突变检测
- 批准号:
6198235 - 财政年份:1999
- 资助金额:
$ 40.2万 - 项目类别:
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Grant-in-Aid for General Scientific Research (C)














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