Impact of social factors on breast cancer biology in African-American women

社会因素对非裔美国女性乳腺癌生物学的影响

基本信息

批准号：
10417207
负责人：
Seema Singh
金额：
$ 59.15万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417207
关键词：
Affect African American African American population Age Alabama Behavior Behavioral Biological Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer Treatment Cancer Biology Cancer Control Catchment Area Cells Chronic Clinical Clinical Management County Data Development Diagnosis Disease Epidemiology Epigenetic Process Evaluation Exhibits Female Florida Gene Expression Gene Expression Regulation Gene-Modified Genes Genetic Transcription Global Change Growth Health Hormones Household Human Biology Hydrocortisone IL6 gene Immune Inflammation Inflammatory Institutes Intervention Leptin Link Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mediating MicroRNAs Minority Groups Mississippi Modification Morphology Outcome Pathogenesis Pathway interactions Patients Phenotype Physiological Population Poverty Prevention Prognosis Publishing Recurrence Regulation Regulator Genes Reporting Research Role Sampling Serum Shoulder Socioeconomic Factors Socioeconomic Status Stress Testing Translating Tumor Biology Tumor Subtype Up-Regulation Woman aggressive breast cancer base behavioral phenotyping cancer health disparity cancer risk caucasian American circulating microRNA cytokine differential expression disadvantaged population disorder risk disparity reduction epigenetic regulation epigenomics experience gene function health disparity health disparity populations high risk human disease improved innovation low socioeconomic status macrophage malignant breast neoplasm minority health disparity mortality obese person racial and ethnic remediation resistin risk prediction social social disadvantage social factors social stress social stressor socioeconomic disadvantage socioeconomics stressor tumor

项目摘要

ABSTRACT African American (AA) women are more likely to be diagnosed at an early age with breast cancer (BC), have aggressive disease and experience greater mortality, compared to their Caucasian American (CA) counterparts. Socioeconomic status (SES) and social stress have long been believed to be the prime cause of such health disparities; however, it is not yet well understood how these social factors are translated into increased cancer risk, aggressive tumor-subtypes, and poor clinical outcomes. Demographic data suggest that AA women encounter more socioeconomic difficulties than CA women and social stressors impact human biology through epigenomic modifications of gene functions. MicroRNAs, which are important epigenetic modulators of gene expression and key players in human biology and disease, are known to be regulated by stress hormones/cytokines and exhibit differential expression in socially disadvantaged population. Along these lines, our published and preliminary studies have identified increased serum levels of inflammatory cytokines and stress hormones (resistin, IL6, leptin, and cortisol), and certain microRNAs (miR-511, miR-27a, and miR-33a) in AA women (with or without BC). We have also observed that treatment of BC cells and macrophages with resistin, IL6, leptin, and cortisol leads to an upregulation of miR-511, miR-27a, and miR-33a, promotes growth and malignant behavior of BC cells, and induces M2 polarization of macrophages. These compelling findings build a strong scientific premise for this project and support our hypothesis that socioeconomic hardships promote chronic inflammation and stress leading to altered serum levels of hormones and cytokines (such as resistin, IL6, leptin, and cortisol), which in turn, modulate the expression of immune-suppressive and tumor- promoting miRNAs, eventually contributing to BC pathogenesis. In four specific aims, we propose to determine global changes in circulating microRNAs in serum of AA and CA women (with or without BC) and establish their correlation with SES (low/moderate/high) (Aim 1); analyze levels of resistin, IL6, leptin, and cortisol in serum, and study their association with SES and serum miRNAs (Aim 2); examine regulation of miRNAs by resistin, IL6, leptin, and cortisol and delineate the underlying mechanisms (Aim 3); and establish the pathobiological significance of differentially-expressed miRNAs (Aim 4). Together, these studies will establish the functional association between socioeconomic health determinants and breast tumor biology, and support the role of miRNAs as epigenomic modifiers that link the social stress to biological phenotypes.

抽象的非裔美国 (AA) 女性更有可能在早期被诊断出患有乳腺癌 (BC)，与白人美国人 (CA) 相比，他们患有侵袭性疾病，死亡率更高。长期以来，社会经济地位（SES）和社会压力一直被认为是造成这种健康的主要原因差异；然而，目前尚不清楚这些社会因素如何转化为癌症增加风险、侵袭性肿瘤亚型和不良的临床结果。人口统计数据表明 AA 女性比加州女性遇到更多的社会经济困难，社会压力源通过以下方式影响人类生物学：基因功能的表观基因组修饰。 MicroRNA，是重要的基因表观遗传调节剂已知人类生物学和疾病的表达和关键参与者受到压力的调节激素/细胞因子，并在社会弱势群体中表现出差异表达。沿着这些思路，我们已发表的初步研究已发现炎症细胞因子的血清水平升高应激激素（抵抗素、IL6、瘦素和皮质醇）和某些 microRNA（miR-511、miR-27a 和 miR-33a） AA 女性（有或没有 BC）。我们还观察到用 BC 细胞和巨噬细胞处理抵抗素、IL6、瘦素和皮质醇导致 miR-511、miR-27a 和 miR-33a 上调，促进生长 BC细胞的恶性行为，并诱导巨噬细胞的M2极化。这些令人信服的发现为该项目奠定坚实的科学前提，并支持我们的假设：社会经济困难促进慢性炎症和压力，导致血清激素和细胞因子水平改变（例如抵抗素、IL6、瘦素和皮质醇），进而调节免疫抑制和肿瘤相关因子的表达促进 miRNA，最终促进 BC 发病机制。在四个具体目标中，我们建议确定 AA 和 CA 女性（伴或不伴 BC）血清中循环 microRNA 的整体变化，并确定其与 SES 的相关性（低/中/高）（目标 1）；分析血清中抵抗素、IL6、瘦素和皮质醇的水平，并研究它们与 SES 和血清 miRNA 的关联（目标 2）；检查抵抗素、IL6 对 miRNA 的调节，瘦素和皮质醇并描绘潜在机制（目标 3）；并建立病理生物学差异表达 miRNA 的重要性（目标 4）。这些研究将共同建立功能性社会经济健康决定因素与乳腺肿瘤生物学之间的关联，并支持 miRNA 作为表观基因组修饰剂，将社会压力与生物表型联系起来。