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.
Socioeconomic factors are suggested to affect gene function and thereby influence health trajectories or modify disease risk in the racial/ethnic minority and health disparity populations. The proposed research will characterize global changes in serum microRNAs (epigenomic regulators of gene expression) of African American women, establish their correlative association with socioeconomic status and physiological stress caused by social hardships, and generate experimental support for these associations at the mechanistic and functional levels. Resulting data is expected to support the role of miRNAs as epigenomic modifiers linking social stress to biological phenotypes, which, in the longer-term, will help in planning effective strategies to reduce existing disparity gaps in the health outcomes.
