Induction of breast cancer in MMTVneu mice

MMTVneu 小鼠乳腺癌的诱导

• 批准号: 6589455
• 负责人: William S Baldwin
• 金额: $ 1.88万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-25 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6589455
• 关键词: breast neoplasms; carbopolycyclic compound; disease /disorder model; environment related neoplasm /cancer; estradiol; estrogen receptors; estrogens; gene expression; gene induction /repression; genetically modified animals; hydroxylation; industrial waste; laboratory mouse; metastasis; model design /development; mouse mammary tumor virus; neoplastic cell; neoplastic growth; northern blottings; pesticides; phenols; phthalates; polymerase chain reaction; steroid hormone metabolism; tissue /cell culture; western blottings

Environmental estrogens, such as PCBs, phthalates, and alkylphenols increase estrogen-responsive growth in vitro. This could play a role in the increase in breast cancer incidence witnessed in developing countries since the industrial revolution. The objective of this study is to examine the carcinogenicity of the environmental estrogen, 4- nonylphenol, in a transgenic mouse model (MMTVneu) with a high propensity for developing primary tumors of the mammary glands and metastasis to the lung. Mice will be treated with 4-nonylphenol for 180- 200 days and then euthanized. Tumor incidence, number, proliferation and metastasis will be compared between treated and untreated mice to determine 4nonylphenol's effects on these parameters. Once a month during the study and following euthanasia, blood will be drawn and circulating estradiol levels will be examined for alterations caused by 4- nonylphenol. Primary tumor tissue will be collected following euthanasia and examined for changes in cell cycle kinetics and production of estrogen response genes such as pS2 and TGFA3. Since 4nonylphenol has significantly greater effects on estrogen-responsive transcription than its estrogen receptor affinity would suggest and it alters steroidogenic P450 levels, it is our theory that 4-nonylphenol alters estradiol metabolism, inactivation and elimination. Therefore, livers will be collected from the mice and estradiol hydroxylation and conjugation will be investigated. Overall, the purpose of this study is to examine 4-nonylphenol's effects on breast cancer growth and its mechanism of action on the mammary tumor.

环境雌激素，如多氯联苯、邻苯二甲酸盐和烷基酚，会增加体外雌激素反应性生长。这可能是工业革命以来发展中国家乳腺癌发病率增加的一个原因。本研究的目的是在转基因小鼠模型（MMTVneu）中检查环境雌激素 4-壬基酚的致癌性，该小鼠模型极有可能发生乳腺原发性肿瘤并转移至肺部。小鼠将被4-壬基苯酚处理180-200天，然后被安乐死。将比较治疗和未治疗小鼠之间的肿瘤发生率、数量、增殖和转移，以确定4壬基酚对这些参数的影响。在研究期间和安乐死后每月一次抽血并检查循环雌二醇水平是否由4-壬基酚引起的改变。安乐死后收集原发性肿瘤组织，并检查细胞周期动力学的变化和雌激素反应基因（例如 pS2 和 TGFA3）的产生。由于 4-壬基苯酚对雌激素反应性转录的影响比其雌激素受体亲和力所显示的影响要大得多，并且它会改变类固醇生成 P450 的水平，因此我们的理论是 4-壬基苯酚会改变雌二醇的代谢、失活和消除。因此，将从小鼠中收集肝脏并研究雌二醇羟基化和缀合。总的来说，本研究的目的是检查 4-壬基酚对乳腺癌生长的影响及其对乳腺肿瘤的作用机制。