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，对环境因素敏感，如吸烟(CS)， 它含有许多具有致突变作用的有毒化学物质，会增加患多种癌症的风险， 包括乳腺癌。电子烟(E-Cigs)是由电池供电的设备，进入 2007年投放市场，为吸烟者提供安全的替代品，并吸引了年轻人口 暴风雨袭来。然而，令人担忧的报道是，E-Cig，无论是否含有尼古丁，也含有 与CS类似，数十种有毒化学物质对健康有害。因此，重要的是要 研究E-Cig对乳腺癌的短期和长期影响的关键因素，即 易受DNA损伤和基因组不稳定的影响。我们在E-Cig裸露乳房中的初步数据 在Balb/c小鼠体内移植的肿瘤MDA-MB-468表现出较高的肿瘤生长速度，并伴随 通过增加活性氧簇(ROS)，降低超氧化物歧化酶(SOD)活性，增加 核因子-kB信号和上调的趋化因子参与免疫逃避。根据我们的初步调查 结果，我们假设E-CIG暴露诱导氧化应激来重新编程癌细胞和 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)E-Cig诱导的氧化应激是否上调Pro- 促进乳腺肿瘤生长的生存途径，以及1)遗传和药理学 氧化应激调节影响E-Cig诱导的乳腺肿瘤生长。E-Cig曝光 非裔美国人(MDA-MB-468和HCC70)和高加索人Balb/c裸鼠移植瘤的研究 (MDA-MB-231和BT549)乳腺癌细胞将被分析肿瘤生长，氧化标记 应激(ROS/SODNRF2/NOX)、肿瘤坏死因子-α/核因子-KB信号与乳腺癌干细胞亚群 (MCSC)。ROS的遗传和药物调控对乳腺肿瘤生长的影响将是 用超氧化物歧化酶、shRNA和抗氧化剂进行评估。目标2：确定-2a)E-Cig是否优先 对癌症/宿主细胞进行重新编程，以促进肿瘤微环境和 促进乳腺癌进展，以及2)CD25单抗治疗 抑制调节性T细胞(Tregs)功能，减少E-Cig介导的乳腺肿瘤 成长。AA和CA TNBC异种移植瘤Balb/c的RNA测序数据(人和小鼠基因) 裸鼠将接受肿瘤/宿主细胞中免疫基因信号的计算分析。 免疫签名将在暴露于E-Cig的转基因MMTV-PyMT小鼠中得到验证 气雾剂/生理盐水。我们还将检测抗CD25单抗治疗对 抑制Tregs和E-Cig诱导的乳腺肿瘤生长。这个项目的成功完成将 促进未来竞争激烈的国家卫生研究院拨款的提交，并增强机构研究能力 建设让CDU本科生和医学生参与生物医学研究的能力。