Cell-Derived Epigenomic Markers of Chronic Stress Distinguish BreastCancer Phenotypes

Breast cancer (BC) is a highly prevalent malignancy in women and is often resistant to available therapies, calling for urgent investigation of the molecular mechanisms underlying its pathogenesis and progression. BC is thought to result from a complex interplay between genetic and environmental factors. Among key factors, chronic stress has been associated with worse cancer outcomes and can profoundly impact the epigenome. However, both stress and BC phenotypes are complex and heterogeneous, making studies that examine their molecular links challenging. Despite their heterogeneity, stressors trigger a neuroendocrine response that in humans culminates in the release of cortisol, a highly lipophilic hormone that traverses essentially every cell and induces widespread genomic effects. Modeling such effects at the epigenetic level, here we examine whether cellular DNA methylation (DNAm) markers of chronic stress - derived from human fibroblasts undergoing prolonged exposure to physiological stress cortisol levels - distinguish BC phenotypes in two independent human cohorts. Our results show that methylomic signatures of stress are consistently higher in tumor samples as compared to normal samples and in more advanced tumor stages and grades. Follow-up analyses further identify specific DNAm sites driving these associations, which are significantly enriched for cell adhesion pathways in both cohorts. These findings provide insights into the molecular mechanisms linking stress with BC and a proof-of-concept for utilizing cell model-derived disease biomarkers in environmental epigenetics.