Developmental Exposures, Stem Cell Reprogramming, and Breast Cancer Disparities

发育暴露、干细胞重编程和乳腺癌差异

• 批准号: 10586452
• 负责人: Justin Adam Colacino
• 金额: $ 64.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586452
• 关键词: African American; American; Award; Basal Cell; Biological Markers; Biology; Breast; Cancer Biology; Carcinogens; Cell Reprogramming; Cells; Characteristics; Chemical Exposure; Chemicals; Chromatin; Communities; Complex; Data; Data Set; Development; Diagnosis; Dichlorodiphenyl Dichloroethylene; Diet; Disparity; Dose; Environment; Epidemiology; Epigenetic Process; Epithelium; Etiology; European; Evaluation; Exercise; Exposure disparity; Exposure to; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Health Services Accessibility; Heavy Metals; Human; Hybrid Cells; Hybrids; Image; In Vitro; Individual; Lead; Link; Malignant Neoplasms; Measures; Mesenchymal; Methods; Michigan; Molecular; Molecular Epidemiology; Molecular Profiling; Molecular Target; Outcome; Parabens; Pathway interactions; Pesticides; Phenotype; Precision therapeutics; Prevention strategy; Reproductive History; Research; Scientist; Testing; Toxic effect; Toxicology; Update; Validation; Woman; aggressive breast cancer; black women; breast stem cell; cancer health disparity; chemical association; cohort; epidemiologic data; epidemiology study; exposed human population; functional outcomes; health disparity; individualized prevention; insight; malignant breast neoplasm; molecular marker; molecular targeted therapies; mortality; mortality risk; novel strategies; outcome disparities; phthalates; racial disparity; social health determinants; stem; stem cell expansion; stem cells; stem-like cell; stemness; toxicant; transcriptomic profiling; transcriptomics; translational impact; treatment strategy; triple-negative invasive breast carcinoma

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.

摘要。此申请是更新R01ES028802， Colacino博士的杰出新环境科学家