Induction of breast cancer in MMTVneu mice

环境雌激素，如多氯联苯，邻苯二甲酸酯和烷基酚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原因之一。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，该模型具有发生乳腺原发性肿瘤和转移至肺的高倾向。小鼠将用4-壬基苯酚处理180- 200天，然后安乐死。将在治疗和未治疗的小鼠之间比较肿瘤发生率、数量、增殖和转移，以确定4-壬基酚对这些参数的影响。在研究期间和人道处死后，每月一次抽血，并检查循环雌二醇水平是否因4-壬基酚引起变化。将在人道处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应答基因（如pS2和TGFA 3）的产生。由于4-壬基酚对雌激素反应性转录的影响显著大于其雌激素受体亲和力，并且它改变了类固醇生成P450水平，因此我们的理论是4-壬基酚改变了雌二醇的代谢、失活和消除。因此，将从小鼠中采集肝脏，并研究雌二醇羟基化和结合。总之，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。

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.