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

摘要 非裔美国人（AA）女性更有可能在早期被诊断患有乳腺癌（BC）， 侵袭性疾病和经验更大的死亡率相比，他们的白人美国人（CA）的同行。 社会经济地位（SES）和社会压力一直被认为是这种健康的主要原因 差异;然而，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临床结局。人口统计数据表明，AA女性 遇到更多的社会经济困难比CA妇女和社会压力影响人类生物学通过 基因功能的表观修饰。microRNA是基因表达的重要表观遗传调节因子， 在人类生物学和疾病中的关键角色，已知受到压力的调节 激素/细胞因子，并在社会弱势群体中表现出差异表达。沿着这些路线， 我们已发表的和初步的研究已经确定炎性细胞因子的血清水平增加， 应激激素（IL-6，瘦素和皮质醇）和某些微RNA（miR-511，miR-27 a和miR-33 a）， AA女性（有或没有BC）。我们还观察到，BC细胞和巨噬细胞的治疗与 IL-6、瘦素和皮质醇导致miR-511、miR-27 a和miR-33 a上调，促进生长 和恶性行为，并诱导巨噬细胞的M2极化。这些令人信服的发现 为这个项目建立一个强有力的科学前提，并支持我们的假设， 促进慢性炎症和应激，导致激素和细胞因子（如 IL-6、瘦素和皮质醇），其反过来调节免疫抑制和肿瘤抑制因子的表达。 促进miRNAs，最终导致BC发病。在四个具体目标中，我们建议确定 AA和CA妇女（有或无BC）血清中循环microRNA的总体变化，并确定其 与SES（低/中/高）的相关性（目的1）;分析血清中的瘦素、IL 6、瘦素和皮质醇的水平， 并研究它们与SES和血清miRNAs的相关性（Aim 2）;检查miRNAs受β-内酰胺酶，IL 6， 瘦素和皮质醇，并描绘了潜在的机制（目的3）;并建立病理生物学 差异表达的miRNAs的意义（Aim 4）。总之，这些研究将建立功能 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 miRNAs作为表观基因组修饰剂，将社会压力与生物表型联系起来。

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.