Developmental Exposures, Stem Cell Reprogramming, and Breast Cancer Disparities

抽象的。此申请是为了更新R 01 ES 028802，Colacino博士的杰出新环境科学家 （一）奖。该项目的目标是确定化学品暴露对乳腺癌的影响 差距。乳腺癌在种族之间存在着巨大的差异。非裔美国女性的平均年龄是2到3岁， 被诊断为最具攻击性的亚型的可能性增加一倍，三阴性，死亡的可能性增加40% 乳腺癌这些差异的病因驱动因素是复杂和多因素的。我们已经确定 美国妇女在多种毒物中化学生物标志物的明显种族差异。我们的初步 数据显示，这些化学物质中的许多具有乳腺癌相关的功能和分子生物活性， 与人体接触有关的剂量。了解化学品暴露差异如何影响侵略性 乳腺癌生物学和乳腺癌死亡率将为我们提供急需的精确策略， 预防和确定新的治疗分子靶点。侵袭性乳腺癌的特征是 癌症的标志的收购，通过环境促进的关键特征， 致癌物。反映在2022年更新的Hallmarks中，来自我们和其他人的数据显示，侵略性乳房 癌症通过发育途径的失调获得“干细胞样”表型， 干细胞的扩增有趣的是，我们的初步数据使用高通量转录组学分析的19个， 这些化学物质表明，多次暴露，包括p，p '-DDE和铅，诱导表型可塑性， 未转化的乳腺细胞。在这里，我们将整合人类暴露数据，公开可用的毒性数据， 高通量体外表征来自不同供体的正常乳腺细胞中的化学效应， 分子流行病学数据集的外部验证。根据我们之前的发现和初步数据， 我们的假设是，这些化学物质将促进癌症的标志和获得干性在人类 相关剂量，并将与乳腺癌死亡率和侵袭性乳腺癌分子 数据区.目标1将量化暴露差异的剂量依赖性功能和转录效应 化学品目标2将定义暴露差异化学品对获得混合干细胞的影响 states.目标3将量化化学暴露在乳腺癌死亡率和结果的差异。我们提出 一种流行病学上知情的精确毒理学方法，我们预计将确定关键的化学物质， 侵袭性乳腺癌及其分子靶点的驱动因素。了解化学品暴露 迫切需要制定新的预防和治疗战略。

Abstract. This application is to renew R01ES028802, Dr. Colacino’s Outstanding New Environmental Scientist (ONES) award. The goal of this project is to define the impacts of chemical exposures on breast cancer disparities. There are profound breast cancer disparities by race. African American women are two to three times more likely to be diagnosed with the most aggressive subtype, triple negative, and 40% more likely to die of breast cancer. The etiological drivers of these disparities are complex and multifactorial. We have identified stark racial disparities in chemical biomarkers in US women across a multitude of toxicants. Our preliminary data show that many of these chemicals have breast cancer associated functional and molecular bioactivity at doses relevant to human exposure. Understanding how chemical exposure disparities impact aggressive breast cancer biology and breast cancer mortality would provide us with much needed strategies for precision prevention and identify new molecular targets for treatment. Aggressive breast cancers are characterized by the acquisition of the Hallmarks of Cancer, promoted by the environmental via the Key Characteristics of Carcinogens. Reflected in the 2022 updated Hallmarks, data from us and others shows that aggressive breast cancers acquire a “stem cell-like” phenotype through dysregulation of developmental pathways or the expansion of stem cells. Intriguingly, our preliminary data using high throughput transcriptomic profiling of 19 of these chemicals shows that multiple exposures, including p,p’-DDE and lead, induce phenotypic plasticity in non-transformed breast cells. Here, we will integrate human exposure data, publicly available toxicity data, and high throughput in vitro characterization of chemical effects in normal breast cells from diverse donors, with external validation in molecular epidemiology datasets. Based on our previous findings and preliminary data, our hypothesis is that these chemicals will promote cancer hallmarks and the acquisition of stemness at human relevant doses and will be associated with breast cancer mortality and aggressive breast cancer molecular profiles. Aim 1 will quantify dose-dependent functional and transcriptional effects of exposure disparity chemicals. Aim 2 will define impacts of exposure disparities chemicals on the acquisition of hybrid stem cell states. Aim 3 will quantify chemical exposure disparities in breast cancer mortality and outcomes. We propose an epidemiologically-informed precision toxicology approach that we expect will determine key chemical drivers of aggressive breast cancers and their molecular targets. Understanding how chemical exposures impact health disparities is urgently needed for new prevention and treatment strategies.