Project Summary/Abstract Title: Molecular Determinants of Social Factors in Prostate Cancer Prostate cancer disproportionately affects African American (AA) men with higher incidence, mortality and aggressive disease. Socioeconomic status (SES) and social stress such as neighborhood factors are widely regarded as the foremost driver of such health disparities however their association and translation to biological stress and mechanisms on pathogenesis are poorly understood. Hypothalamic-pituitary-adrenal axis (HPA) modulates stress response and has been suggested to mediate social stress induced effects on cellular physiology racial disparities in cancer outcomes. HPA-axis modulates cortisol levels controlling the glucocorticoid (GC) response following a social stress. In addition to cortisol, Leptin levels have been also demonstrated as effectors of stress response. Such stress hormones can modulate cancel cell signaling affecting pathogenesis and outcomes. MicroRNAs are epigenetic elements that are highly stable noncoding small 21-23nt gene- regulatory RNAs acting primarily by targeting 3?UTRs; their roles have been studied in cancer cell survival, proliferation, and metastasis as well as biomarkers of resistance and aggressive PCa. We have recently identified racially distinct differentially expressed miRNAs in PCa tissues and body fluids (serum and urine) as potential biomarker. Both Glucocorticoid and leptin signaling have been shown to affect the expression of miRNAs in human and laboratory models. In this proposal, we will test the hypothesize that social and neighborhood factors translate into continuous biological stress perturbing the levels of stress hormones such as cortisol and leptin resulting in alteration of epigenetic machinery including expression of miRNAs. The proposal will analyze circulating microRNAs and stress hormone levels in African American (AA) prostate cancer patients of the Washington DC metro area with differential socioeconomic status and social stress. Next, we will study the interplay between stress hormones and selected microRNAs in modulating cancer hallmarks. Finally, we will study miRNA-targets-stress markers by identifying miRNA targets and pathways involved to mechanistically characterize selected miRNAs for pathways modulated during social stress. This study will bridge the gap between social factors and biological determinants by studying logical epigenetic mechanisms modulated by social stress and causing health disparities. Understanding these biological implications of social stress will significantly impact diagnosis, prognosis and treatment development for aggressive PCa in African Americans.

R01MD012767

2017-09-26

2022-07-31