Does Runx1 Suppress Breast Cancer Stemness by mediating higher order chromatin organization?
Does Runx1 Suppress Breast Cancer Stemness by mediating higher order chromatin organization?
批准号:
9897629
负责人:
Andrew J Fritz
金额:
$7.14万
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:
已结题
起止时间:
2018-04-06 至 2021-07-05
关键词:
ArchitectureAutomobile DrivingBinding SitesBiologicalBiological AssayBreast Cancer CellBreast Cancer PatientBreast Epithelial CellsCD44 geneCRISPR interferenceCancer EtiologyCancer RelapseCell ProliferationCell modelCellsChIP-seqChromatinChromatin Remodeling FactorDNADataDifferentiation and GrowthEnhancersExpression ProfilingFatty acid glycerol estersFibrinogenFlow CytometryFutureGene ExpressionGenesGenomeGenomicsHormonalHumanIL8 geneInjectionsJAK2 geneKaryotypeLuciferasesMCF10A cellsMammary NeoplasmsMammary glandMediatingMediator of activation proteinModelingMolecular ConformationMusNucleic Acid Regulatory SequencesOutcomeOutcome StudyPLAUR genePathologyPathway interactionsPhenotypeProcessPropertyProteinsRUNX1 geneRefractoryRegulationRegulator GenesRegulatory ElementRelapseReporterResistanceResolutionRoleSignal PathwaySolidSorting - Cell MovementStructureTestingTumorigenicitybreast cancer progressioncancer initiationcancer stem cellcareercell motilitychemotherapychromatin remodelingchromosome conformation captureclinically relevantcofactorconventional therapycytokinedriver mutationepithelial to mesenchymal transitionfunctional outcomesgenetic signaturein vivoinsightknock-downloss of functionmalignant breast neoplasmnoveloutcome forecastoverexpressionpremalignantpreventpromoterrecruitself-renewalstemstemnesssubcutaneoustheoriestranscription factortranscriptome sequencingtumortumor growthtumor progression
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Elucidating the role of the RUNX1 transcription factor in control of chromatin architecture and genomic regulation
in breast cancer initiation is meaningful from a biological perspective, and has potential to be clinically relevant.
RUNX1 interacts with mediators of signaling pathways, chromatin remodeling factors, and chromatin organizing
proteins at gene regulatory regions to coordinate cell proliferation, growth and differentiation. Our recent results
indicate that RUNX1 functions to decrease tumor growth, prevent epithelial to mesenchymal transition, mediate
higher-order chromatin organization, and suppress key genes implicated in breast cancer stem cell (BCSC)
pathology. My preliminary results suggest that RUNX1 suppresses PI3K and MTOR pathway genes (eg. PIK3R1,
PIK3C2A, SOS1), cytokines (eg. IL1a, CXCL8, JAK2) and other key genes (eg. HIF1a, UPAR, and ZEB1) and
a novel subset of genes that were identified by RNA-seq comparing BCSCs to non-BCSCs. BCSCs are capable
of self-renewal, drive tumor growth, resist chemotherapy, and cause cancer relapse. Consistent with the putative
role of RUNX1 in these processes, low RUNX1 expression in breast tumors is associated with poor prognosis.
My central hypothesis is that RUNX1 regulates expression of target genes that are dysregulated in BrCa
progression, and that its role in mediating higher-order chromatin organization is essential to these
functions. I propose to determine the mechanisms by which RUNX1 functions in basal breast cancer, with an
emphasis on its influence on BCSCs (CD24-low/CD44+high) versus non-BCSCs (CD24+high/CD44-low). The
regulation of key genes specifically within non-BCSCs or BCSCs will be established by flow sorting followed by
qPCR, and ChIP-qPCR for RUNX1 binding sites nearby these genes. The impact of RUNX1 loss on early stage
breast cancer progression and BCSCs will be determined using murine mammary fat pad injection. Next, we will
examine the role of RUNX1 in mediating enhancer regulation and higher order chromatin organization of these
key genes in BCSCs, and how this organization is altered by depleting RUNX1 in normal and early-stage breast
cancer cells. These studies will employ high-throughput, high resolution capture chromatin conformation capture
(capture Hi-C). I hypothesize that BCSCs present an altered higher order chromatin organization, consistent with
their stem-like expression profile, and that the loss of RUNX1 induces higher order chromatin organization that
is more stem-like for these key genes. Mechanistic insight into genome architecture and expression in basal
breast cancer cells and BCSCs will enhance capabilities for selectively targeting breast tumors, as well as
BCSCs that are refractory to conventional treatments. These studies will form a solid basis for my future career
focus on genomic organization and expression in cancer initiation and progression.
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会议论文
Supplement to AWD32581 - Fritz fellowship F32CA220935
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批准号:10377016
-
项目类别:
-
资助金额:$1.73万
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财政年份:2021
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负责人:Andrew J Fritz
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依托单位:
海外基金