HUMAN MAMMARY STROMA AS A TARGET FOR ORGANOCHLORINES

人类乳腺基质作为有机氯的目标

• 批准号: 7335977
• 负责人: Sakina Elzebair Eltom
• 金额: $ 10.34万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7335977
• 关键词: HUMAN; MAMMARY; STROMA; TARGET; ORGANOCHLORINES

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Although the overall breast cancer (BC) incidence rate for African American (AA) women is lower than for White women, among AA women under the age of 45 the rates are higher. The inherited forms of BC account only for 5-10% of all cases, leaving 90-95% of all cases to be contributed by environmental factors, including chemical exposure. Work in this laboratory is focused on determining how exposures to environmental chemicals such as organochlorines are conferring not only increased risk of breast cancer among young African American women but also the presentation of a more aggressive form of the disease with a higher mortality rates than in white women. This proposal will test the hypothesis that the disparite exposure of AA women to higher levels of organochlorines than White women and the persistence of these chemicals in their breast adipose tissues will modify the stromal function resulting in disruption of stromal-epithelial interaction, which leads to deregulation of epithelial growth and differentiation. The following three specific aims will be addressed using an in vitro cell culture system of human mammary epithelia and stromal fibroblasts from African American and white women donors. Aim 1. To characterize the heterogeneity of breast epithelia and fibroblasts with respect to their estrogen-responsiveness and how is it modified by exposure to organochlorines. Aim 2. To verify that activation of estrogen receptors by organochlorines affects expression of stromal growth factors, which determine their growth and epithelial growth. Aim 3. To identify the stromal factors expressed in response to estrogens and their modification by organochlorines exposure, by evaluating global gene expression of cytokines, growth factors, extracellular matrix components, proteases and angiogenic factors using specialized oligonucleotide microarray chips; and by protein expression profiling of both synthesized and secreted proteins using comparative proteomics. Such studies will provide mechanistic approach for how these hormonally active chemicals target the mammary stromal epithelial interaction to induce breast carcinogenesis.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。摘要尽管非裔美国人(AA)女性的总体乳腺癌发病率低于白人女性，但在45岁以下的AA女性中，发病率更高。遗传型BC只占所有病例的5%-10%，所有病例的90%-95%是由环境因素造成的，包括化学暴露。该实验室的工作重点是确定接触有机氯等环境化学品不仅会增加年轻的非裔美国女性患乳腺癌的风险，还会导致一种比白人女性更高死亡率的更具侵袭性的疾病的出现。这项提议将检验这样一种假设，即AA女性与白人女性相比，暴露在更高水平的有机氯中，以及这些化学物质在她们乳房脂肪组织中的持久性将改变间质功能，导致间质-上皮相互作用中断，从而导致上皮生长和分化的放松调控。使用来自非洲裔美国人和白人女性捐赠者的人乳腺上皮细胞和基质成纤维细胞的体外细胞培养系统，将解决以下三个具体目标。目的1.研究乳腺上皮细胞和成纤维细胞对雌激素反应的异质性，以及有机氯对乳腺上皮细胞和成纤维细胞的影响。目的2.验证有机氯激活雌激素受体影响基质生长因子的表达，基质生长因子决定基质生长因子的生长和上皮生长。目的3.通过使用专门的寡核苷酸微阵列芯片评估细胞因子、生长因子、细胞外基质成分、蛋白水解酶和血管生成因子的整体基因表达，以及通过比较蛋白质组学对合成和分泌蛋白质的蛋白质表达谱进行分析，鉴定雌激素及其修饰对基质因子表达的影响。这些研究将为这些荷尔蒙活性化学物质如何靶向乳腺间质上皮相互作用诱导乳腺癌的发生提供机制方法。