title: 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.
authors.affiliation: UCLA Department of Psychology, 1285 Franz Hall, P.O. Box 951563, Los Angeles, CA 90095-1563, United States. jbower@ucla.edu
authors.forename: Julienne E
authors.initials: JE
authors.lastname: Bower
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ganz
authors.forename: Michael R
authors.initials: MR
authors.lastname: Irwin
authors.forename: Jesusa M G
authors.initials: JM
authors.lastname: Arevalo
authors.forename: Steve W
authors.initials: SW
authors.lastname: Cole
mesh_terms: D001943:Breast Neoplasms / Q000150:complications* / Q000235:genetics*; D019295:Computational Biology; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005221:Fatigue / Q000209:etiology* / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005938:Glucocorticoids / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007962:Leukocytes / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D017741:Survivors
chemical_list: D005938:Glucocorticoids; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012313:RNA; D006854:Hydrocortisone