Electronic cigarettes, oxidative stress and development of breast tumor

电子烟、氧化应激与乳腺肿瘤的发生

• 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
• 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

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.

摘要 乳腺癌是一种复杂的疾病，对环境因素如香烟烟雾（CS）敏感， 它含有许多有毒的化学物质，这些化学物质是诱变性的，并增加了许多癌症的风险， 包括乳腺癌电子烟（E-cigarettes）是一种电池供电的设备， 市场在2007年提供了一个安全的替代吸烟者，并采取了年轻人口 被暴风雨袭击然而，令人担忧的报告正在出现，电子烟，有或没有尼古丁，也含有 与CS类似，大量有害健康的有毒化学物质。因此， 研究导致电子烟对乳腺癌的短期和长期影响的关键因素， 易受DNA损伤和基因组不稳定性的影响。我们在电子烟暴露乳房的初步数据 Balb/c小鼠中的癌症MDA-MB-468异种移植物表明更高的肿瘤生长，这伴随着 通过增加活性氧（ROS），降低超氧化物歧化酶（SOD）活性，增加 NF-κ B信号传导和上调的趋化因子参与免疫逃避。根据我们初步的 研究结果，我们假设电子烟暴露诱导氧化应激重新编程癌细胞， 肿瘤微环境促进乳腺癌生长。我们将在这些条件下测试我们的假设。 具体目的：目的1：确定1A）电子烟诱导的氧化应激是否上调了前列腺素原。 促进乳腺肿瘤生长的存活途径，和1B）遗传和药理学 氧化应激的调节影响E-Cig诱导的乳腺肿瘤生长。电子烟暴露 在来自非裔美国人（MDA-MB-468和HCC 70）和高加索人的Balb/c裸鼠中的异种移植物 将分析（MDA-MB-231和BT549）乳腺癌细胞的肿瘤生长、氧化应激标志物和肿瘤标志物。 应激（ROS/SOD/Nrf 2/NOX）、TNF-α/NF-KB信号转导与乳腺癌干细胞亚群 （MCSC）。ROS的遗传和药理学操作对乳腺肿瘤生长的影响将是 通过SOD shRNA和抗氧化剂评估。目的2：确定是否-2A）电子烟优先 重新编程癌症/宿主细胞以促进肿瘤微环境内的免疫逃避， 促进乳腺癌进展，和2B）用CD 25单克隆抗体治疗 抑制调节性T细胞（TcB）功能，减少E-Cig介导的乳腺肿瘤 增长来自AA和CA TNBC异种移植物Balb/c的RNA测序数据（人和小鼠基因） 对裸鼠进行肿瘤/宿主细胞中免疫基因特征的计算分析。 将在暴露于E-Cig的转基因MMTV-PyMT小鼠中验证免疫特征 气雾剂/盐水。我们还将研究抗CD 25单克隆抗体治疗对 抑制甲状腺激素和电子烟诱导的乳腺肿瘤生长。该项目的成功完成将 促进提交具有高度竞争力的未来NIH赠款，并提高机构研究能力 建设从事CDU本科生和医学生在生物医学研究。