Interactions between ES-miRNAs and environmental risk factors are responsible for TNBC progression and associated racial health disparities: a novel analysis with multilevel moderation inferences

ES-miRNA 和环境风险因素之间的相互作用导致 TNBC 进展和相关种族健康差异：一项采用多级调节推论的新颖分析

• 批准号: 10594746
• 负责人: Yaguang Xi
• 金额: $ 33.63万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594746
• 关键词: Acute; Address; Affect; African American; African American population; Animal Model; Bioinformatics; Biological; Blood; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cancer Patient; Cancer Prognosis; Cause of Death; Characteristics; Chronic; Data; Development; Diagnosis; Disease Progression; Distant Metastasis; Elements; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Ethnic Origin; Ethnic Population; Exposure to; Genes; Goals; High Prevalence; Human; In Vitro; Incidence; Individual; Inherited; Link; Lipids; Louisiana; Malignant Neoplasms; Measures; Mediating; Mediation; Messenger RNA; Metastatic breast cancer; Methods; MicroRNAs; Modeling; Molecular Biology; Neighborhoods; Neoplasm Metastasis; Oncogenic; Outcome; Patients; Physical environment; Play; Population; Prognosis; Proteins; Race; Recurrence; Reporting; Role; Sampling; Social Environment; Socioeconomic Status; Stromal Cells; Structure; Survival Rate; Tumor Promotion; Tumor-Derived; United States; Visceral metastasis; Woman; Xenograft procedure; breast cancer progression; caucasian American; clinical translation; cohort; epidemiology study; exosome; health care availability; health disparity; in vivo Model; innovation; insight; malignant breast neoplasm; miRNA expression profiling; mortality; neoplastic cell; novel; outcome prediction; patient derived xenograft model; predictive modeling; racial disparity; racial health disparity; racial population; regression trees; risk prediction; social; socioeconomics; statistics; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor progression

Project Summary: For women in the United States, breast cancer is not only the most common malignancy but also the second leading cause of death. In this application, we focus on a specific subtype of breast cancer known as triple- negative breast cancer (TNBC). Because TNBC has a higher recurrence rate and poorer overall mortality than other subtypes of breast cancer, it is more aggressive and extremely difficult to treat with standard therapies. Epidemiological studies have clearly shown that African American (AA) women are more likely to develop advanced TNBC than Caucasian American (CA) women. For instance, in Louisiana (LA), where we live, from 2010 to 2017, there were 3,790 TNBC cases, of which 1,861 (49.1%) were from the AA population versus 1,900 (50.1%) were from the CA population, while 32.8% of the LA population were AA and 62.8% were CA. Notably, 43.5% of the AA patients were diagnosed with regional or distant metastasis, compared with 36.6% of CA patients. Thus, TNBC represents a significant challenge to racial health disparities in Louisiana. The overall goal of this project is to determine the extent to which modifiable factors in the neighborhood physical and social environment affect the prognosis of TNBC patients and whether their effects can be accurately reflected and quantified through detectable biological variables. Recent studies have revealed that tumor-derived exosomes (TDEs) play a prominent role in promoting tumor progression and metastasis. TDEs contain many oncogenic elements, including multiple miRNAs, mRNAs, proteins, and lipids. Notably, exosomal miRNAs (ES-miRs) have been reported to be critical for crosstalk between tumor cells and stromal cells in the tumor microenvironment (TME) and the establishment of pre-metastatic niches. Therefore, we hypothesize that ES-miRs are biological variables that not only reflect and quantify the effects of environmental risk factors associated with racial health disparities, but are also functionally involved in the progression of TNBC. Our specific aims are as follows: Aim 1: Use multilevel mediation and moderation analysis to identify significant ES-miRs and environmental risk factors for TNBC progression and understand how their interactions explain racial health disparities in TNBC. Aim 2: Validate the function of selected ES-miRs in TNBC progression using in vitro and in vivo models. Aim 3: Develop a new model to predict TNBC progression in AA and CA patients. We expect that our study can develop an innovative approach to quantify adverse physical and social environmental influences on the progression of TNBC across different races and provide insights into the development of more effective strategies to reduce racial health disparities in TNBC.

项目概要： 对于美国的女性来说，乳腺癌不仅是最常见的恶性肿瘤， 主要死因在这个应用程序中，我们专注于一个特定的亚型乳腺癌称为三重- 阴性乳腺癌（TNBC）。因为TNBC的复发率更高，总体死亡率更低， 与其他亚型的乳腺癌相比，它更具侵袭性，并且非常难以用标准疗法治疗。 流行病学研究清楚地表明，非洲裔美国人（AA）妇女更容易发展 与高加索美国（CA）女性相比，例如，在我们居住的路易斯安那州， 2010年至2017年，共有3，790例TNBC病例，其中1，861例（49.1%）来自AA人群，而1，900例来自AA人群。 (50.1 CA人群中AA占32.8%，CA占62.8%。值得注意的是， 43.5%的AA患者有局部或远处转移，CA患者有36.6%有局部或远处转移 患者因此，TNBC代表了路易斯安那州种族健康差异的重大挑战。总目标 这个项目的目的是确定在多大程度上可改变的因素在附近的物理和社会 环境对TNBC患者预后的影响以及其影响是否能准确反映， 通过可检测的生物变量进行量化。最近的研究表明，肿瘤来源的外泌体 （TDE）在促进肿瘤进展和转移中起显著作用。TDE含有许多致癌的 元件，包括多种miRNA、mRNA、蛋白质和脂质。值得注意的是，外泌体miRNAs（ES-miRs）具有 据报道，在肿瘤微环境中肿瘤细胞和基质细胞之间的串扰是关键的 (TME)和转移前小生境的建立。因此，我们假设ES-miR是生物学上的， 变量不仅反映和量化与种族相关的环境风险因素的影响， 健康差异，但也在功能上参与了TNBC的进展。我们的具体目标是 目标1：使用多层次中介和适度分析来识别重要的ES-miR， TNBC进展的环境风险因素，并了解它们的相互作用如何解释种族健康 TNBC的差异。目的2：使用体外和免疫组织化学方法，验证所选ES-miR在TNBC进展中的功能。 体内模型目的3：开发一种新的模型来预测AA和CA患者的TNBC进展。我们预计 我们的研究可以开发一种创新的方法来量化不利的物理和社会环境影响 关于TNBC在不同种族中的进展，并为更有效的 减少TNBC中种族健康差异的战略。