Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue

Abstract

Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n=11) and non-fatigued controls (n=10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids (p<.05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors.

Fig. 1

Differential gene expression in fatigued versus non-fatigued breast cancer survivors. Affymetrix Human Gene 1.0 ST high-density oligonucleotide arrays identified 119 genes relatively up-regulated in fatigued survivors, and 318 genes up-regulated in non-fatigued survivors (red indicates over-expression, green indicates under-expression) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.).

Fig. 2

Transcriptional activity of NF-κB and GR signaling pathways. Results of TELiS bioinformatics analyses showed significantly greater density of NF-κB response elements (2A), and significantly lower density of glucocorticoid response elements (2B) in the promoters of genes up-regulated in fatigued versus non-fatigued breast cancer survivors.