Developmental Exposures, Stem Cell Reprogramming, and Breast Cancer Disparities

抽象的。本申请书旨在续签科拉西诺博士杰出的新环境科学家R01ES028802 (一)奖。这个项目的目标是确定化学物质暴露对乳腺癌的影响。 差距。不同种族的乳腺癌差异很大。非裔美国女性的年龄在2到3岁之间 更有可能被诊断为最具侵袭性的亚型，三重阴性，死亡可能性增加40% 乳腺癌的风险。这些差异的病因是复杂的和多因素的。我们已经确定了 美国女性在多种毒物中的化学生物标记物存在明显的种族差异。我们的预赛 数据显示，其中许多化学物质具有与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攻击性 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 获得癌症的特征，由环境通过关键的特征促进 致癌物质。反映在2022年更新的标志中，来自我们和其他人的数据显示，攻击性乳房 癌症通过发育途径的失调获得一种类似干细胞的表型 干细胞的扩增。耐人寻味的是，我们的初步数据使用了19个高通量转录图谱 这些化学物质表明，多次暴露，包括p，p‘-DDE和铅，可以诱导小鼠的表型可塑性 未转化的乳房细胞。在这里，我们将整合人体暴露数据、公开的毒性数据和 来自不同捐赠者的正常乳腺细胞化学效应的高通量体外表征 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特征和人类干细胞的获得。 相关剂量，并将与乳腺癌死亡率和侵袭性乳腺癌分子相关 配置文件。目标1将量化暴露差异的剂量依赖的功能和转录效应 化学制品。目标2将确定接触不同化学品对混合干细胞获取的影响 各州。AIM 3将量化乳腺癌死亡率和预后中的化学暴露差异。我们建议 一种流行病学知情的精确毒理学方法，我们预计将确定关键化学物质 侵袭性乳腺癌的驱动因素及其分子靶点。了解化学暴露是如何 新的预防和治疗战略迫切需要影响健康差距。

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.