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，在体外促进雌激素反应的生长。这可能对工业革命以来发展中国家乳腺癌发病率的增加起到一定作用。本研究的目的是检测环境雌激素4-壬基酚在转基因小鼠模型(MMTVneu)中的致癌性，该模型具有发生乳腺原发肿瘤和肺转移的高倾向。小鼠将被4-壬基苯酚处理180-200天，然后安乐死。将比较治疗和未治疗的小鼠的肿瘤发病率、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，将抽取血液，并检查循环中的雌二醇水平是否由4-壬基酚引起的变化。原发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和雌激素反应基因的产生，如PS2和TGFA3。由于4-壬基酚对雌激素反应转录的影响明显大于其雌激素受体亲和力，并改变了类固醇合成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，将从小鼠身上采集肝脏，并对雌二醇的羟化和结合进行研究。总体而言，本研究的目的是研究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.