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：
SHEHLA PERVIN
金额：
$ 14.35万
依托单位：
CHARLES R. DREW UNIVERSITY OF MED & SCI
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：
https://reporter.nih.gov/project-details/10629814
关键词：
Address African American Antibody Therapy Antioxidants BALB/c Nude Mouse Behavior Biomedical Research Breast Cancer Cell CCL22 gene CD8B1 gene CXCL10 gene Carcinogens Caucasians Cell physiology Cells Cigarette Smoker Complex Computer Analysis Cysteine DNA Damage Data Development Devices Disease Electronic cigarette Ensure Environmental Risk Factor Epidemic Experimental Designs Exposure to Flow Cytometry Future Genes Genetic Genomic Instability Grant Growth Health Health Hazards Human IL2RA gene Immune Immune Evasion Inbred BALB C Mice Injections Institution Long-Term Effects MDA MB 231 MDA-MB-468 Malignant Neoplasms Mammary Neoplasms Marketing Mediating Mediator Medical Students Molecular Molecular Target Monoclonal Antibodies Mouse Mammary Tumor Virus Mus NF-kappa B Nicotine Oxidative Stress Oxidative Stress Induction Oxides Pathway interactions Poison Population Predisposition Prognosis Publishing Reactive Oxygen Species Regulatory T-Lymphocyte Reporting Research Risk Role Saline Signal Pathway Signal Transduction Superoxide Dismutase TNF gene Testing Tissues Transgenic Organisms Tumor Promotion Tumor Volume Tumor Weights United States National Institutes of Health Up-Regulation Woman Xenograft Model Xenograft procedure Youth breast cancer progression cancer cell cancer diagnosis cancer risk cancer stem cell chemokine cigarette smoke combustible cigarette e-cigarette aerosols e-cigarette smoke electronic cigarette use embryonic stem cell ethnic difference experimental study genetic signature implantation innovation malignant breast neoplasm mortality multiplex assay neoplastic cell nicotine exposure nitrosative stress pharmacologic polyoma middle tumor antigen programs rapid growth small hairpin RNA student training transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment tumor progression tumorigenesis undergraduate 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，对诸如香烟烟雾（CS）等环境因素敏感其中包含许多具有诱变的有毒化学物质，并增加了许多癌症的风险，包括乳腺癌。电子烟（电子烟）是输入电池的设备 2007年的市场为吸烟者提供安全的替代品，并吸引了年轻的人口暴风雨。但是，关于报告的报道正在出现，无论有或没有尼古丁，e-cig都包含与CS相似，数十种对健康有害的有毒化学物质。因此，重要的是检查主要参与者对电子烟对乳腺癌的短期和长期影响的贡献，这就是容易受到DNA损伤和基因组不稳定性的影响。我们在电子烟暴露乳房中的初步数据 BALB/c小鼠中的癌症MDA-MB-468 Xenographtics表明肿瘤的生长更高，已完成通过增加活性氧（ROS），超级氧化物歧化酶（SOD）活性减少，增加 NF-KB信号传导和更新的免疫抗性趋化因子。基于我们的初步调查结果，我们假设电子烟暴露会诱导氧化应激以重编程癌细胞和肿瘤微环境可促进乳腺癌的生长。我们将在这些下测试我们的假设具体目的：目标1：确定1A）电子烟诱导的氧化应激是否上调促进乳腺肿瘤生长的生存途径，以及1B）遗传和药理氧化应激的调节会影响E-CIG诱导的乳腺肿瘤生长。电子烟暴露了来自非裔美国人（MDA-MB-468和HCC70）和高加索人的BALB/C裸鼠的异种移植物（MDA-MB-231和BT549）将分析乳腺癌细胞的肿瘤生长，氧化标志物应力（ROS/SOD/NRF2/NOX），TNF-α/NF-KB信号传导和乳腺癌干细胞的子集（MCSC）。 ROS的遗传和药物操纵对乳腺肿瘤生长的影响将是通过SOD SHRNA和抗氧化剂评估。目标2：确定-2a）e-cig是否优先确定重新制作癌症/宿主细胞以促进肿瘤微环境内的免疫环境和促进乳腺癌的进展，2B）用CD25单克隆抗体处理抑制调节性T细胞（TREG）功能并降低E-CIG介导的乳腺肿瘤生长。来自AA和Ca TNBC Xenographictics BALB/C的RNA测序数据（针对人和小鼠基因）裸鼠将接受肿瘤/宿主细胞中免疫基因特征的计算分析。免疫特征将在暴露于E-cig的转基因MMTV-PYMT小鼠中进行验证气溶胶/盐水。我们还将检查抗CD25单克隆抗体治疗对抑制Tregs和E-CIG诱导的乳腺肿瘤生长。成功完成该项目将促进提交竞争激烈的未来NIH赠款并提高机构研究能力建造与CDU本科生和医学生有关生物医学研究的建设。