Molecular causes and mechanistic underpinning of breast cancer racial disparity
乳腺癌种族差异的分子原因和机制基础
基本信息
- 批准号:9245643
- 负责人:
- 金额:$ 34.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAfrican AmericanApoptosisAreaBindingBinding ProteinsBiologicalBiological AssayBiological MarkersBreast Cancer CellBreast Cancer PatientBreast Cancer TreatmentBreast Cancer cell lineCancer PatientCancer cell lineCaucasiansCell CommunicationCell LineCell ProliferationCellsCharacteristicsClinicalDataDeletion MutationDiseaseDisease OutcomeDown-RegulationDrug TargetingGenetic TranscriptionGrowthHistologicInfiltrationInflammatoryInterleukin 6 ReceptorInterleukin-6InterventionLeadLinkLuciferasesMDA MB 231MDA-MB-468Malignant NeoplasmsMammary Gland ParenchymaMammary NeoplasmsMapsMeasuresMediatingMediator of activation proteinMicroRNAsMolecularMolecular ProfilingMonitorMutation AnalysisNeoplasm MetastasisNude MiceOutcomePathologicPathway interactionsPatientsPerceptionPhenotypePhosphorylationPlayProductionPublic HealthRNA InterferenceRaceRecurrenceRegulatory ElementReporterResearchResistanceRiskRoleSTAT3 geneSamplingSerumSiteTestingTherapeuticTissuesTumor BiologyUnited StatesUp-RegulationWomanXenograft procedureaggressive therapybasebreast cancer diagnosisbreast densitycancer cellcancer health disparitycaucasian Americanclinically relevantcytokinedensityepithelial to mesenchymal transitionexperienceexperimental studyhigh riskin vivo imaginginsightknock-downmacrophagemalignant breast neoplasmmortalitymouse modelneoplastic cellnoveloutcome forecastoverexpressionpromoterpublic health relevanceracial differenceracial disparityreceptorreceptor for advanced glycation endproductsresistinresponsestemnesstherapy resistanttranscription factortriple-negative invasive breast carcinomatumortumor microenvironment
项目摘要
DESCRIPTION (provided by applicant): African American (AA) women are more likely to have aggressive breast cancer (BC) and experience greater mortality rates as compared to Caucasian (CA) women. Another upsetting fact is that this cancer outcome gap has continued to widen over past several years underscoring the immediate need to make progress in this area. It is being increasingly appreciated that tumor microenvironment (TME) may play an important role in BC racial disparity; however, underlying molecular and mechanistic basis is not clearly understood. This project is built upon our novel findings suggesting the existence of a TME-tumor cell interaction-driven regulatory loop, which is predominantly active in AA patients. We demonstrate that 1) serum levels of inflammatory cytokines, resistin and IL6, are significantly elevated in AA BC patients compared to their CA counterparts, 2) AA BCs have significantly greater expression and phosphorylation of STAT3 compared to CA BCs, 3) treatment of triple-negative breast cancer (TNBC) cell lines from both AA and CA patients with resistin promotes expression of STAT3/pSTAT3 and enhances IL6 production, thus suggesting a dominant role of differential TME in overall disease outcome, 4) IL6 mediates the effect of resistin on STAT3 phosphorylation, 5) resistin promotes aggressive tumor phenotypes and therapy-resistance in BC cells through STAT3 induction, 6) resistin also upregulates LIN28A, a regulator of stemness, and downregulates let-7 miRNA, and 7) LIN28A silencing abrogates resistin-induced upregulation of IL6, pSTAT3 and STAT3. Based on these findings, we hypothesize that intrinsic differences in tumor biology contributes to BC racial disparity and resistin-LIN28A-(IL6)- STAT3/pSTAT3 serves as an important regulatory loop controlling the aggressive and therapy-resistant phenotypes of BC cells. This hypothesis will be tested in three specific aims. In aim 1, we will characterize the molecular mechanisms underlying resistin-LIN28A-(IL6)-STAT3/pSTAT3 regulatory loop by examining the pathways regulating resistin-induced LIN28A expression, and whether LIN28A mediates resistin-induced let-7 downregulation, which then leads to STAT3 and IL6 upregulation in BC cells. In aim 2, we will examine the functional significance of this regulatory by using luciferase-tagged, control or LIN28A-/STAT3-silenced BC cell lines and characterize the response of resistin and its downstream effectors on growth, metastasis and therapy-resistance in an orthotopic nude mice model. In aim 3, we will determine the clinical relevance of the components of resistin-LIN28A-(IL6)-STAT3/pSTAT3 regulatory loop in BC racial disparity by examining their expression in clinical samples and assessing their correlation (alone and in combination) with TME and tumor cell characteristics as well as with race and patient's survival. Together, these studies will provide novel insight into molecular causes and mechanistic underpinning of BC racial disparity and provide novel set of biomarkers and potential drug-targets to develop novel ways for reducing the widening gaps in clinical outcome of AA and CA BC patients.
描述(由适用提供):与高加索(CA)妇女相比,非裔美国人(AA)妇女更有可能患有侵略性乳腺癌(BC),并经历更高的死亡率。另一个令人沮丧的事实是,在过去的几年中,这种癌症结果差距持续了很大,强调了在这一领域取得进展的迫切需求。越来越多地认为,肿瘤微环境(TME)可能在BC种族差异中起重要作用。但是,尚未清楚地理解潜在的分子和机械基础。该项目建立在我们的新发现之上,表明存在TME肿瘤细胞相互作用驱动的调节环,该环路在AA患者中主要是活跃的。我们证明1)AA BC患者的炎性细胞因子的血清水平显着升高,与CA的同伴相比,2)AA BC的STAT3表达和磷酸化的表达和磷酸化明显更高,与CA BC相比,与TNBC Cell 3和CA的表达相比,AA和CA的表达(TNBC)/AA AA的表达(TNBC)/AA AA AA AA AA AA和CA的表达(TNBC)的表达更高(TNBC)。 IL6 production, thus suggesting a dominant role of differential TME in overall disease outcome, 4) IL6 mediates the effect of resistin on STAT3 phosphorylation, 5) resistin promotes aggressive tumor phenotypes and therapy-resistance in BC cells through STAT3 induction, 6) resistance also upregulates LIN28A, a regulator of stemness, and downregulates let-7 miRNA, and 7) LIN28A沉默的Acrogates抵抗蛋白引起的IL6,PSTAT3和STAT3的上调。基于这些发现,我们假设肿瘤生物学的内在差异有助于BC种族差异和抵抗素-LIN28A-(IL6) - STAT3/PSTAT3是控制BC细胞的积极和治疗抗药性表型的重要调节循环。该假设将以三个特定目的进行检验。在AIM 1中,我们将通过检查调节抵抗蛋白诱导的LIN28A表达的途径来表征抵抗蛋白LIN28A-(IL6)-STAT3/PSTAT3调节环的分子机制,以及LIN28A是否介导了抗蛋白诱导的LET-7下调,然后导致STAT3和IL6 UPCALUMENTINPRECTIAN cTAT3和IL6上升。在AIM 2中,我们将通过使用荧光素酶标记的,对照或Lin28A-/STAT3脱毛的BC细胞系来检验该调节的功能意义,并表征抵抗素及其对正常裸体小鼠模型中的抗蛋白及其对生长,转移和治疗耐药性的影响。在AIM 3中,我们将通过检查BC种族差异的临床差异来确定抵抗蛋白LIN28A-(IL6)-STAT3/PSTAT3/PSTAT3调节循环的临床相关性,通过检查其在临床样本中的表达并评估其相关性并单独评估其与TME和TME和肿瘤细胞的相关性(与TME和肿瘤细胞的结合)以及竞赛和患者的生存和生存性。总之,这些研究将提供有关BC种族差异的分子原因和机械基础的新见解,并提供新型的生物标志物和潜在的药物目标,以开发新的方法来减少AA和CA CA BC患者临床结果的扩大差距。
项目成果
期刊论文数量(0)
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Seema Singh其他文献
Seema Singh的其他文献
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{{ truncateString('Seema Singh', 18)}}的其他基金
Impact of social factors on breast cancer biology in African-American women
社会因素对非裔美国女性乳腺癌生物学的影响
- 批准号:
10213668 - 财政年份:2019
- 资助金额:
$ 34.66万 - 项目类别:
Impact of social factors on breast cancer biology in African-American women
社会因素对非裔美国女性乳腺癌生物学的影响
- 批准号:
10417207 - 财政年份:2019
- 资助金额:
$ 34.66万 - 项目类别:
Impact of social factors on breast cancer biology in African-American women
社会因素对非裔美国女性乳腺癌生物学的影响
- 批准号:
10640127 - 财政年份:2019
- 资助金额:
$ 34.66万 - 项目类别:
Molecular causes and mechanistic underpinning of breast cancer racial disparity
乳腺癌种族差异的分子原因和机制基础
- 批准号:
9922879 - 财政年份:2016
- 资助金额:
$ 34.66万 - 项目类别:
Molecular causes and mechanistic underpinning of breast cancer racial disparity
乳腺癌种族差异的分子原因和机制基础
- 批准号:
9094145 - 财政年份:2016
- 资助金额:
$ 34.66万 - 项目类别:
Chemoprotective role of silver nanoparticles in UV radiation-induced skin carcino
银纳米粒子在紫外线辐射诱发的皮肤癌中的化学保护作用
- 批准号:
8704599 - 财政年份:2014
- 资助金额:
$ 34.66万 - 项目类别:
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