HUMAN MAMMARY STROMA AS A TARGET FOR ORGANOCHLORINES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。尽管非裔美国人（AA）女性的乳腺癌（BC）总发病率低于白人女性，但45岁以下的AA女性的发病率更高。遗传形式的BC仅占所有病例的5-10%，其余90-95%的病例是由环境因素造成的，包括化学品暴露。该实验室的工作重点是确定接触环境化学物质（如有机氯）如何不仅增加了年轻非洲裔美国妇女患乳腺癌的风险，而且呈现出比白人妇女死亡率更高的更具侵袭性的疾病形式。这一提议将验证这样一个假设，即AA女性比白人女性暴露于更高水平的有机氯，以及这些化学物质在乳房脂肪组织中的持续存在，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。以下三个具体目标将利用非裔美国人和白人妇女供体的人乳腺上皮细胞和间质成纤维细胞的体外细胞培养系统来解决。目的1。表征乳腺上皮细胞和成纤维细胞雌激素反应的异质性，以及暴露于有机氯后如何改变雌激素反应。目标2。验证有机氯激活雌激素受体影响基质生长因子的表达，基质生长因子决定雌激素受体的生长和上皮细胞的生长。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，确定基质因子对雌激素的表达及其在有机氯暴露下的修饰；并通过比较蛋白质组学分析合成和分泌蛋白的蛋白质表达谱。这些研究将为这些激素活性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。

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.