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（例如PCB，邻苯二甲酸盐和烷基酚）在体外会增加雌激素反应性的生长。自工业革命以来，这可能会在发展中国家见证的乳腺癌发病率的增加中发挥作用。这项研究的目的是检查转基因小鼠模型（MMTVNEU）中环境雌激素4-北苯酚的致癌性，其对乳腺的原发性肿瘤的倾向很高，肺部转移到肺部。小鼠将用4-北苯酚治疗180-200天，然后安乐死。将在处理过的小鼠和未处理的小鼠之间比较肿瘤的发生率，数量，增殖和转移，以确定4Nonylphenol对这些参数的影响。在研究期间和安乐死之后，每月一次，将吸收血液，并将检查循环雌二醇水平的循环水平，以了解由4-北苯酚引起的改变。原发性肿瘤组织将在安乐死后收集，并检查细胞周期动力学的变化以及雌激素反应基因（如PS2和TGFA3）的产生。由于4Nonylphenol对雌激素反应性转录的影响明显高于其雌激素受体亲和力的影响，并且它会改变类固醇生成P450水平，因此我们的理论认为4-北苯酚可以改变雌二醇代谢，灭活和消除。因此，将从小鼠中收集肝脏，并研究雌二醇羟基化，并研究结合。总体而言，这项研究的目的是检查4-北苯酚对乳腺癌生长的影响及其对乳腺肿瘤的作用机理。