Depression, social support, and beta-adrenergic transcription control in human ovarian cancer

Abstract

Motivated by previous indications that beta-adrenergic signaling can regulate tumor cell gene expression in model systems, we sought to determine whether similar dynamics occur in primary human ovarian cancer. DNA microarray analyses of 10 ovarian carcinomas identified 266 human transcripts that were differentially expressed in tumors from patients with elevated biobehavioral risk factors (high depressive symptoms and low social support) relative to grade-and stage-matched tumors from low-risk patients. Promoter-based bioinformatic analyses confirmed increased activity of several beta-adrenergically-linked transcription control pathways, including CREB/ATF, NF-κB/ Rel, STAT, and Ets family transcription factors. Consistent with increased beta-adrenergic signaling, high biobehavioral risk patients also showed increased intra-tumor concentrations of norepinephrine (but no difference in plasma norepinephrine). These data show that genome-wide transcriptional profiles are significantly altered in patients with high behavioral risk profiles, and they identify betaadrenergic signal transduction as a likely mediator of those differences.

Computational identification of gene–social environment interaction at the humanIL6locus

“…1 and Fig. 2), intratumor NE levels were also elevated in tissues from patients experiencing high levels of social adversity (mean = 19.5 ± 6.9 pg NE /mg tissue vs. <0.1 ± 0.1 in low-adversity conditions; difference, P = 0.0482) (42). Histological mapping showed that perivascular nerve fibers with occasional parenchymal radiations constituted the primary source of intratumor NE (Fig.…”

“…2E). To confirm the relevance of those findings for human social adversity, we carried out similar analyses in primary ovarian carcinoma tissues resected from women experiencing high levels of depression and low social support vs. minimal depressive symptoms and high social support (42) (Tables S3 and S4). Results again indicated up-regulated GATA1 activity in association with social adversity (Fig.…”

“…Briefly, adversity-sensitive genes were identified using microarray gene expression profiling, and promoters of those genes were tested for over-representation of GATA1 TFBMs as previously described (17) (TRANSFAC V$GATA1_01 position-specific weight matrix, −300 bp core promoter sequence, mat_sim ≥ 0.90). Differential gene transcription was assayed by Affymetrix high-density oligonucleotide arrays in (i) CNS prefrontal cortex and CD11b+ splenocytes from adult male C57BL/6 mice (Charles River Laboratories) subject to three daily cycles of 2-h exposure to social threat vs. nonthreatening control conditions (58), and (ii) human ovarian carcinoma tissues resected from patients confronting high vs. low levels of social adversity as previously described (42). Procedures were approved by Institutional Animal Care and Use Committees and study site Institutional Review Boards (42).…”

“…Computational details of these analyses are provided in SI Text. Briefly, candidate ERTFs were identified through TELiS bioinformatics analysis (17) of TF-binding motifs (TFBMs) in promoters of genes that were found to be empirically differentially expressed in CNS prefrontal cortex tissue or CD11b + splenocytes from animals that were subject to experimentally imposed social threat (described below) or in solid tissue samples from humans subject to chronic social adversity as previously described (42). The IL6 core promoter sequence was then computationally scanned for potential regulatory SNPs (rSNPs) predicted to affect the binding of candidate ERTFs.…”

Expression Profiles of Loneliness-associated Genes for Survival Prediction in Cancer Patients

“…In 2007, Cole et al, first provided that subjective social isolation was associated with human genome-wide transcriptional activity, including inhibiting anti-inflammatory transcription and promoting proinflammatory pathways (Cole et al, 2007). Furthermore, Lutgendorf et al (2009) validated that high depression and low social support was relative to increased activity of β-adrenergic transcription control, which promotes tumor progression in ovarian cancer. With gene expression of a genome, survival prediction in cancer patients was improved over histologic grades.…”