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出患有乳腺癌(BC)， 与他们的高加索美国人(CA)同行相比，他们患上了侵略性疾病，经历了更高的死亡率。 长期以来，社会经济地位和社会压力一直被认为是导致这种健康的主要原因 差异；然而，目前还不清楚这些社会因素是如何转化为癌症增加的 风险、侵袭性肿瘤亚型和较差的临床结果。人口统计数据表明，再生障碍性贫血女性 遇到比CA女性更多的社会经济困难，社会应激源通过 基因功能的表观基因组修饰。MicroRNAs--重要的基因表观遗传调控因子 在人类生物学和疾病中的表达和关键角色，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不同的表达。沿着这些思路， 我们已发表的和初步的研究发现，血清中炎性细胞因子水平和 应激激素(抵抗素、白介素6、瘦素和皮质醇)和某些microRNAs(miR-511、miR-27a和miR-33a)在 AA妇女(有或没有BC)。我们还观察到，BC细胞和巨噬细胞的处理 抵抗素、白介素6、瘦素和皮质醇导致miR-511、miR-27a和miR-33a表达上调，促进生长 和BC细胞的恶性行为，并诱导巨噬细胞M2极化。这些令人信服的发现 为这个项目建立强有力的科学前提，并支持我们的假设，即社会经济困难 促进慢性炎症和压力，导致血清激素和细胞因子水平改变(如 抵抗素、白介素6、瘦素和皮质醇)，它们反过来调节免疫抑制和肿瘤- 促进miRNAs，最终促进BC的发病。在四个具体目标中，我们建议确定 AA和CA妇女(伴或不伴BC)血清循环microRNAs的整体变化及其意义 与SES(低/中/高)相关(目标1)；分析血清抵抗素、IL-6、瘦素和皮质醇水平， 并研究它们与SES和血清miRNAs的关系(目标2)；检测抵抗素、IL6、 瘦素和皮质醇，并描述潜在的机制(目标3)；并建立病理生物学 差异表达miRNAs的意义(目标4)。总之，这些研究将建立起功能 社会经济健康决定因素与乳腺肿瘤生物学之间的关系，并支持 MiRNAs作为表观基因组修饰物，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.