Epigenetic Modulation of PTPG by Zeranol in Beef Increases Breast Cancer Risk

Zeranol（Z）是一种具有雌激素活性（E2）的非甾体药物，用作厌氧生长促进剂 在美国牛肉行业。食用含生物活性Z的牛肉对人体健康具有潜在的风险 和乳腺癌细胞。以前的工作表明，PTP γ（PTPG）是一个E2调节的乳腺癌， 抑癌基因Z能够在mRNA和蛋白水平下调PTPG， 人正常和癌变乳腺组织和细胞。要评估的总体假设是， 食用来自Z植入肉牛的牛肉产品可能会对健康产生潜在影响 对人类消费者的影响，特别是在生殖内分泌学和乳房敏感性方面 组织中 具体目的：（1）：确定原代培养正常人的表观遗传和基因表达改变 乳腺上皮细胞、基质细胞和组织暴露于从Zimplanted采集的血清和肉提取物中 小母牛(2)：定义雌激素诱导的乳腺肿瘤ACI中的DNA甲基化变化 大鼠模型暴露于由Z植入的肉牛配制的含生物活性Z的饮食。(3)探讨 雌激素诱导的乳腺肿瘤ACI大鼠模型中的乳腺肿瘤发生 消耗低水平的含生物活性Z的实验饮食，所述实验饮食由从以下动物收集的肉配制： 植入Z基因的小母牛。 研究人员团队在3个领域聚集专业知识，系统地研究Z的促有丝分裂作用， 生殖和激素敏感的乳房。这些包括Z（Lin）的体外和体内效应的建模， 基因启动子中全局和独特表观遗传改变的作图和定量（Huang & Yan）， 和整体基因表达的比较定量和生物标志物的鉴定（Wick）。 意义：所提出的实验将提供生物活性膳食Z和PTPG之间的明确联系 通过PTPG表达的表观遗传调节下调至最终的肿瘤发生， 肿瘤相关基因为了将我们的研究结果从实验室工作台转化到床边， 将通过蛋白质组学分析进一步验证体外实验的结果。我们的目的是提供 综合数据（Z植入期间和从小母牛中取出Z后的暴露水平）， 提高人们对环境暴露于雌激素模拟物、牛肉生长促进剂、Z.

Zeranol (Z) is a non-steroidal agent with estrogenic activity (E2) that is used as an anobolic growth promoter in the U.S. beef industries. Consumption of bio-active Z containing-beef has a potential risk in human normal and cancerous breast cells. Previous work suggests that PTP gamma (PTPG) is an E2-regulated breast cancer suppressor gene. Z is capable in down-regulating the PTPG both in mRNA and protein levels in human normal and cancerous breast tissues and cells. The overall HYPOTHESIS to be evaluated is that the consumption of beef products, derived from Z-implanted beef cattle may possess a potential health impact on human consumers, particularly with respect to reproductive endocrinology and hormone-sensitive breast tissues. Specific Aims: (1): Define epigenetic and gene expression alterations in primary cultured normal human breast epithelial cells, stromal cells, and tissues exposed to serum and meat extracts collected from Zimplanted beef heifers. (2): Define DNA methylation changes in the estrogen inducible mammary tumor ACI rat model exposed to bio-active Z-containing diets formulated from Z-implanted beef heifers. (3) Investigate mammary tumorigenesis in the estrogen inducible mammary tumor ACI rat model after long-term consumption of low level of bio-active Z containing experimental diets formulated from meat collected from Z- implanted beef heifers. The team of researchers assembles expertise in 3 areas to systematically study the mitogenic effects of Z in reproductive and hormone sensitive breast. These include modeling of in vitro and in vivo effects of Z (Lin), mapping and quantification of global and unique epigenetic alterations in gene promoters (Huang & Yan), and comparative quantification of global gene expression and identification of biomarkers (Wick). Significance: The proposed experiments will provide a clear linkage between bio-active dietary Z and PTPG down-regulation to eventual tumorigenesis via epigenetic regulation of the expression of PTPG and other tumor relevant genes. To translate our findings from bench top to bedside, selected biomarkers uncovered from the in vitro experiments will be further validated by proteomic analysis. It is our intent to provide comprehensive data (exposure levels during Z-implantation and after Z withdrawal from the beef heifers) to raise awareness of environmental exposure to the estrogen mimic, beef growth promoter, Z.