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

玉米赤霉醇(Z)是一种具有雌激素活性(E2)的非甾体类药物，用作厌氧生长促进剂 在美国牛肉行业。食用生物活性含锌牛肉对人体健康有潜在风险 和癌变的乳腺细胞。以前的研究表明，PTP伽马(PTPG)是一种受E2调节的乳房 抑癌基因。Z能够下调PTPG在mRNA和蛋白水平的表达。 人类正常和癌变的乳腺组织和细胞。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和激素敏感乳房方面 纸巾。 具体目标：(1)：确定原代培养的正常人的表观遗传学和基因表达变化 乳房上皮细胞、间质细胞和组织暴露于血清和从植入物中收集的肉类提取物中 小母牛。(2)：确定雌激素诱导的乳腺癌ACI中DNA甲基化的变化 以Z-植入肉牛配制的含Z生物活性饲料喂养大鼠模型。(三)调查 雌激素诱导的大鼠乳腺癌ACI模型长期致瘤性的研究 低水平含生物活性Z的试验性日粮的摄入量 Z-植入的小牛肉。 研究小组汇集了3个领域的专业知识，系统地研究了Z在体内的促分裂作用 对生殖和激素敏感的乳房。这些包括对Z(LIN)的体外和体内效应的模拟， 基因启动子的全球和独特表观遗传改变的定位和量化(黄和严)， 以及全球基因表达的比较量化和生物标记物的识别(WICK)。 意义：拟议的实验将提供生物活性膳食Z和PTPG之间的明确联系 通过对PTPG和其他基因表达的表观遗传调控来下调最终的肿瘤发生 肿瘤相关基因。为了将我们的发现从工作台转移到床边，发现了一些选定的生物标记物 来自体外实验的结果将通过蛋白质组学分析进一步验证。我们的意图是提供 综合数据(植入Z期间和停用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的认识。

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.