Electronic cigarettes, oxidative stress and development of breast tumor
电子烟、氧化应激与乳腺肿瘤的发生
基本信息
- 批准号:10629814
- 负责人:
- 金额:$ 14.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-05 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAfrican AmericanAntibody TherapyAntioxidantsBALB/c Nude MouseBehaviorBiomedical ResearchBreast Cancer CellCCL22 geneCD8B1 geneCXCL10 geneCarcinogensCaucasiansCell physiologyCellsCigarette SmokerComplexComputer AnalysisCysteineDNA DamageDataDevelopmentDevicesDiseaseElectronic cigaretteEnsureEnvironmental Risk FactorEpidemicExperimental DesignsExposure toFlow CytometryFutureGenesGeneticGenomic InstabilityGrantGrowthHealthHealth HazardsHumanIL2RA geneImmuneImmune EvasionInbred BALB C MiceInjectionsInstitutionLong-Term EffectsMDA MB 231MDA-MB-468Malignant NeoplasmsMammary NeoplasmsMarketingMediatingMediatorMedical StudentsMolecularMolecular TargetMonoclonal AntibodiesMouse Mammary Tumor VirusMusNF-kappa BNicotineOxidative StressOxidative Stress InductionOxidesPathway interactionsPoisonPopulationPredispositionPrognosisPublishingReactive Oxygen SpeciesRegulatory T-LymphocyteReportingResearchRiskRoleSalineSignal PathwaySignal TransductionSuperoxide DismutaseTNF geneTestingTissuesTransgenic OrganismsTumor PromotionTumor VolumeTumor WeightsUnited States National Institutes of HealthUp-RegulationWomanXenograft ModelXenograft procedureYouthbreast cancer progressioncancer cellcancer diagnosiscancer riskcancer stem cellchemokinecigarette smokecombustible cigarettee-cigarette aerosolse-cigarette smokeelectronic cigarette useembryonic stem cellethnic differenceexperimental studygenetic signatureimplantationinnovationmalignant breast neoplasmmortalitymultiplex assayneoplastic cellnicotine exposurenitrosative stresspharmacologicpolyoma middle tumor antigenprogramsrapid growthsmall hairpin RNAstudent trainingtranscriptome sequencingtriple-negative invasive breast carcinomatumortumor growthtumor microenvironmenttumor progressiontumorigenesisundergraduate student
项目摘要
Abstract
Breast cancer is a complex disease that is sensitive to environmental factors like cigarette smoke (CS),
which contains many toxic chemicals that are mutagenic and increases the risk of many cancers,
including breast cancer. Electronic cigarettes (E-Cigs) are battery-powered devices that entered the
market in 2007 to provide a safe alternative for cigarette smokers and has taken the younger population
by storm. However, concerning reports are emerging that E-Cig, with or without nicotine, also contains
similar to CS, scores of toxic chemicals that are deleterious to health. Therefore, it is important to
examine key players that contribute to short and long-term effects of E-Cig on breast cancer, which is
susceptible to DNA damage and genomic instability. Our preliminary data in E-Cig exposed breast
cancer MDA-MB-468 xenografts in Balb/c mice indicates higher tumor growth, which was accompanied
by increased reactive oxygen species (ROS), reduced super oxide dismutase (SOD) activity, increased
NF-kB signaling and upregulated chemokines implicated in immune evasion. Based on our preliminary
findings, we hypothesize that E-Cig exposure induces oxidative stress to reprogram cancer cells and
tumor microenvironment to promote breast cancer growth. We will test our hypothesis under these
Specific Aims: Aim 1: To determine whether 1A) E-Cig-induced oxidative stress up-regulates pro-
survival pathways to promote breast tumor growth, and 1B) Genetic and pharmacological
modulation of oxidative stress influences E-Cig-induced breast tumor growth. E-Cig exposed
xenografts in Balb/c nude mice from African American (MDA-MB-468 and HCC70) and Caucasian
(MDA-MB-231 and BT549) breast cancer cells will be analyzed for tumor growth, markers for oxidative
stress (ROS/SOD/Nrf2/NOX), TNF-α/NF-KB signaling and subset of mammary cancer stem cells
(MCSC). Effect of genetic and pharmacological manipulation of ROS on breast tumor growth will be
assessed by SOD shRNA and anti-oxidants. Aim 2: To determine whether- 2A) E-Cig preferentially
re-programs cancer/host cells to facilitate immune evasion within tumor microenvironment and
promote breast cancer progression, and 2B) Treatment with CD25 monoclonal antibody
suppresses regulatory T cells (Tregs) function and reduces E-Cig-mediated breast tumor
growth. RNA sequencing data (for human and mouse genes) from AA and CA TNBC xenografts Balb/c
nude mice will be subjected to computational analysis for immune gene signatures in tumor/host cells.
The immune signatures will be validated in transgenic MMTV-PyMT mice exposed to E-Cig
aerosol/saline. We will also examine the effect of anti-CD25 monoclonal antibody treatment on
suppression of Tregs and E-Cig-induced breast tumor growth. Successful completion of this project will
facilitate submission of highly competitive future NIH grants and enhance institutional research capacity
building to engage CDU undergraduate and medical students in biomedical research.
抽象的
乳腺癌是一种复杂的疾病,对香烟烟雾 (CS)、
其中含有许多有毒化学物质,这些化学物质具有致突变性,会增加患多种癌症的风险,
包括乳腺癌。电子烟(E-Cigs)是进入市场的电池供电设备
2007 年推出的市场为吸烟者提供了安全的替代品,并吸引了年轻人
暴风雨。然而,令人担忧的报道称,无论含有或不含尼古丁的电子烟也含有
与CS类似,有数十种对健康有害的有毒化学物质。因此,重要的是
研究电子烟对乳腺癌短期和长期影响的关键因素,即
容易受到 DNA 损伤和基因组不稳定的影响。我们在电子烟暴露乳房方面的初步数据
Balb/c 小鼠中的癌症 MDA-MB-468 异种移植物表明肿瘤生长较高,同时伴随着
通过增加活性氧 (ROS)、降低超氧化物歧化酶 (SOD) 活性、增加
NF-kB 信号传导和上调趋化因子与免疫逃避有关。根据我们的初步
研究结果表明,我们假设电子烟暴露会诱导氧化应激来重新编程癌细胞,
肿瘤微环境促进乳腺癌生长。我们将在这些条件下检验我们的假设
具体目标: 目标 1:确定 1A) 电子烟诱导的氧化应激是否上调亲-
促进乳腺肿瘤生长的生存途径,以及 1B) 遗传和药理学
氧化应激的调节影响电子烟诱导的乳腺肿瘤生长。电子烟曝光
非裔美国人(MDA-MB-468 和 HCC70)和白种人 Balb/c 裸鼠的异种移植
(MDA-MB-231 和 BT549)将分析乳腺癌细胞的肿瘤生长、氧化标记物
应激 (ROS/SOD/Nrf2/NOX)、TNF-α/NF-KB 信号传导和乳腺癌干细胞亚群
(MCSC)。 ROS 对乳腺肿瘤生长的遗传和药理学操作的影响将是
通过 SOD shRNA 和抗氧化剂进行评估。目标 2:确定是否优先 - 2A) 电子烟
重新编程癌症/宿主细胞以促进肿瘤微环境中的免疫逃避
促进乳腺癌进展,2B) 使用 CD25 单克隆抗体治疗
抑制调节性 T 细胞 (Treg) 功能并减少电子烟介导的乳腺肿瘤
生长。来自 AA 和 CA TNBC 异种移植物 Balb/c 的 RNA 测序数据(针对人类和小鼠基因)
裸鼠将对肿瘤/宿主细胞中的免疫基因特征进行计算分析。
免疫特征将在暴露于电子烟的转基因 MMTV-PyMT 小鼠中进行验证
气雾剂/盐水。我们还将检查抗 CD25 单克隆抗体治疗对
抑制 Tregs 和电子烟诱导的乳腺肿瘤生长。该项目的顺利完成将
促进提交竞争激烈的未来 NIH 拨款并增强机构研究能力
大楼吸引基民盟本科生和医学生参与生物医学研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('SHEHLA PERVIN', 18)}}的其他基金
Beige Adipocytes and African American Breast Tumors
米色脂肪细胞和非裔美国人乳腺肿瘤
- 批准号:
10202503 - 财政年份:2018
- 资助金额:
$ 14.35万 - 项目类别:
Targeting pERK1/2 in Human Mammary Cancer Stem Cells
靶向人类乳腺癌干细胞中的 pERK1/2
- 批准号:
8078639 - 财政年份:2011
- 资助金额:
$ 14.35万 - 项目类别:
Targeting pERK1/2 in Human Mammary Cancer Stem Cells
靶向人类乳腺癌干细胞中的 pERK1/2
- 批准号:
8677817 - 财政年份:2011
- 资助金额:
$ 14.35万 - 项目类别:
Targeting pERK1/2 in Human Mammary Cancer Stem Cells
靶向人类乳腺癌干细胞中的 pERK1/2
- 批准号:
8881968 - 财政年份:2011
- 资助金额:
$ 14.35万 - 项目类别:
Targeting pERK1/2 in Human Mammary Cancer Stem Cells
靶向人类乳腺癌干细胞中的 pERK1/2
- 批准号:
8299474 - 财政年份:2011
- 资助金额:
$ 14.35万 - 项目类别:
Targeting pERK1/2 in Human Mammary Cancer Stem Cells
靶向人类乳腺癌干细胞中的 pERK1/2
- 批准号:
8509637 - 财政年份:2011
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- 批准号:
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