In Utero TCDD Programming for Mammary Cancer

乳腺癌子宫内 TCDD 编程

• 批准号: 6740247
• 负责人: CORAL LAMARTINIERE
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-18 至 2006-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740247
• 关键词: DNA methylation; breast neoplasms; cancer risk; chemical related neoplasm /cancer; dioxins; embryo /fetus toxicology; estrogen receptors; gene expression; genetic promoter element; glutathione transferase; growth inhibitors; laboratory rat; mammary gland; matrix assisted laser desorption ionization; methyltransferase; neoplasm /cancer genetics; protein biosynthesis; proteomics; two dimensional gel electrophoresis

DESCRIPTION (provided by applicant): We have demonstrated that in utero exposure of rats to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) suppresses the development of chemically induced mammary cancer in the adult female offspring. We have shown that mammary gland maturation accounts for the cellular mechanism of mammary cancer susceptibility. However, little is known about the underlying mechanisms at the genome and protein levels. We hypothesize that in utero exposure to TCDD acts via imprinting mechanism to alter the mammary gland proteome that in turn determines cancer susceptibility. The Specific Aim 1 is to investigate DNA methylation as imprinting mechanism of in utero TCDD exposure predisposing for mammary cancer susceptibility. From mammary glands of prepubertal and adult rats exposed in utero + TCDD, we will investigate DNA methyltransferases (Dnmts) and DNA base methylation of specific genes containing large CpG rich promoter regions. Hypermethylation is associated with gene silencing. We will focus our attention on estrogen receptor alpha (ER-alpha), glutathione S transferase-pi (GST-pi) and mammary derived growth inhibitor (MDGI). The protein products of these genes have been associated with the early stages of mammary cancer development. Aim 2 is to identify proteins that are differentially expressed in mammary glands of rats exposed in utero to TCDD Characterization of proteins that are differentially expressed during the period of mammary gland differentiation (day 21) and at time of carcinogen exposure (day 50) in the DMBA-rat model (in the absence of the original chemical modulator, TCDD) will identify proteins that predetermine mammary cancer susceptibility. We will identify differentially expressed proteins from mammary glands using 2-D gel electrophoresis and MALDI-TOF spectrometry Identification of methylated gene promoters and individual proteins/protein clusters that are differentially expressed will aid in understanding how in utero exposure to environmental chemicals can program predisposition for cancer.

描述（由申请人提供）：我们已经证明，在将大鼠暴露于2,3,7,8四氯迪本佐-P-二恶英（TCDD）中，可以抑制成年女性后代化学诱导的乳腺癌的发展。我们已经表明，乳腺成熟是乳腺癌易感性的细胞机制。然而，对于基因组和蛋白质水平下的基本机制知之甚少。 我们假设在子宫中暴露于TCDD的行动是通过印记机制改变乳腺蛋白质组的，而乳腺蛋白质组反过来决定了癌症的易感性。具体目的1是将DNA甲基化作为子宫TCDD暴露于乳腺癌易感性的烙印机制。在暴露于子宫内 + TCDD中的青春期前和成年大鼠的乳腺中，我们将研究DNA甲基转移酶（DNMTS）和含有大型CPG富启动子区域的特定基因的DNA碱基甲基化。高甲基化与基因沉默有关。我们将注意力集中在雌激素受体α（ER-Alpha），谷胱甘肽转移酶-PI（GST-PI）和乳腺衍生的生长抑制剂（MDGI）上。这些基因的蛋白质产物与乳腺癌发展的早期阶段有关。 Aim 2 is to identify proteins that are differentially expressed in mammary glands of rats exposed in utero to TCDD Characterization of proteins that are differentially expressed during the period of mammary gland differentiation (day 21) and at time of carcinogen exposure (day 50) in the DMBA-rat model (in the absence of the original chemical modulator, TCDD) will identify proteins that predetermine mammary cancer敏感性。我们将使用2-D凝胶电泳和MALDI-TOF光谱法鉴定甲基化基因启动子和单个蛋白质/蛋白簇的鉴定，这些蛋白质将鉴定出乳腺中差异表达的蛋白质，这些蛋白质差异表达，这些蛋白质蛋白会有助于理解子宫内对环境化学物质在环境化学物质中如何在环境化学物质中如何为癌症编程。