Epigenetic profile of women with breast cancer exhibiting a proinflammatory phenotype

Abstract

We recently reported that women with breast cancer who experienced childhood adversity exhibit more intense and persistent elevations in behavioral symptoms and circulating proinflammatory cytokines from diagnosis through early survivorship. Here we evaluated histone post translational modifications (PTMs) associated with this proinflammatory phenotype. Women with breast cancer completed psychological and childhood adversity measures, and provided blood for isolation of peripheral blood mononuclear cells (PBMC) for immune and epigenetic analysis. We analyzed trajectories of outcomes, across diagnosis to 6-months post-cancer treatment, using hierarchical linear modeling. Findings revealed that greater exposure to childhood adversity was related to higher levels of perceived stress, depressive symptoms, fatigue and sleep disturbance; as well as, higher levels of circulating and PBMC produced IL-6 and TNF-alpha. Analysis of PTMs demonstrated intranuclear H3K9Ac associated with increased IL-6 production by CD14+, TNF-alpha by CD8+ and increased plasma TNF-alpha levels for CD56+ PBMC. H4K8Ac was associated with increased circulating and produced TNF-alpha for CD8 + PBMC. Further, exposure to neglect and abuse was related to histone modification, and these histone modifications were predictive of a greater proinflammatory response from cancer diagnosis through 6 months post-cancer treatment. In conclusion, women with breast cancer exposed to childhood adversity experience more behavioral symptoms and exhibit a proinflammatory phenotype, which related to histones H3K9Ac and H4K8Ac. Histone PTMs may underlie vulnerability for a proinflammatory phenotype in women with breast cancer.