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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。摘要尽管非裔美国人（AA）妇女的乳腺癌（BC）总发病率低于白色妇女，但在45岁以下的AA妇女中，发病率较高。BC的遗传形式仅占所有病例的5-10%，剩下90-95%的病例由环境因素（包括化学品暴露）引起。该实验室的工作重点是确定暴露于环境化学品（如有机氯）如何不仅增加了年轻非裔美国妇女患乳腺癌的风险，而且还呈现出比白色妇女死亡率更高的更具侵略性的疾病形式。该提案将检验以下假设：AA女性的亚硝酸盐暴露水平高于白色女性，且这些化学物质在其乳房脂肪组织中的持久性将改变基质功能，导致基质-上皮相互作用的破坏，从而导致上皮生长和分化的失调。将使用来自非裔美国人和白色女性供体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来解决以下三个具体目标。目标1.描述乳腺上皮细胞和成纤维细胞雌激素反应性的异质性，以及暴露于有机氯如何改变其雌激素反应性。目标2.验证有机氯对雌激素受体的激活影响基质生长因子的表达，而基质生长因子决定基质生长和上皮生长。目标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、蛋白酶和血管生成因子的全球基因表达，以及通过使用比较蛋白质组学对合成和分泌蛋白进行蛋白质表达谱分析，确定基质因子对雌激素的反应及其通过有机氯暴露进行的修饰。这些研究将为这些具有生物活性的化学物质如何靶向乳腺间质上皮相互作用以诱导乳腺癌的发生提供机制途径。