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

项目总结： 对于美国女性来说，乳腺癌不仅是最常见的恶性肿瘤，也是第二大恶性肿瘤 头号死因。在本应用程序中，我们重点关注一种特定的乳腺癌亚型，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 对于其他亚型乳腺癌，它更具侵袭性，用标准疗法治疗极其困难。 流行病学研究清楚地表明，非裔美国人(AA)妇女更有可能患上 比高加索美国人(CA)女性更高的TNBC。例如，在我们居住的路易斯安那州，来自 2010至2017年，共有3,790例TNBC病例，其中1,861例(49.1%)来自再生障碍性贫血人群，而同期为1,900例 (50.1%)来自CA群体，而LA群体中32.8%是AA，62.8%是CA。值得注意的是， 43.5%的AA患者被诊断为区域或远处转移，而CA患者的这一比例为36.6% 病人。因此，TNBC是对路易斯安那州种族健康差距的重大挑战。总目标 这个项目的目的是确定社区、物理和社会中的可改变因素的程度 环境影响TNBC患者的预后，其影响是否能准确地反映和 通过可检测的生物变量进行量化。最近的研究表明，肿瘤来源的外切体 (TDES)在促进肿瘤进展和转移方面发挥着重要作用。TDEs含有许多致癌物质 元素，包括多个miRNAs、mRNAs、蛋白质和脂质。值得注意的是，外体miRNAs(ES-miR)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至关重要的 (TME)和建立转移前利基。因此，我们假设ES-miR是生物学的。 不仅反映和量化与种族相关的环境风险因素的影响的变量 卫生方面的差距，但在功能上也参与了TNBC的进展。我们的具体目标是 目标1：使用多层次调解和缓和分析，以确定重要的ESMRs和 TNBC进展的环境风险因素，并了解它们的交互作用如何解释种族健康 TNBC中的差异。目的2：在体外和体外实验中验证选定的ES-miRs在TNBC进展中的作用 活体模型。目的：建立预测再生障碍性贫血(AA)和尖锐湿疣(CA)患者TNBC进展的新模型。我们期待着 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 关于跨不同种族的TNBC的进展，并为开发更有效的 减少TNBC种族健康差距的战略。

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.