Abstract
The link between depression and breast cancer outcomes has been a topic of great interest for the last decade and up-regulated inflammatory signaling may be one of the biological mechanisms at play. The purpose of this study was to examine the relationship between depression severity levels, and pro-inflammatory cytokines interleukin – 1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) in tandem with a pathway involving the receptor for advanced glycation end products (RAGE) 2-10 weeks post-surgery, and 1 year later. Activation of RAGE by ligands S100A8/A9 can trigger pathways that lead to the production of pro-inflammatory cytokines. To date, no studies have linked depression with RAGE ligands nor tested whether these S100A8/A9 ligands act as an intermediary between depressive symptoms and pro-inflammatory cytokine up-regulation in breast cancer patients. Women in the South Florida area (ages 32-69) with Stage 0-III breast cancer (N = 240) were recruited 2 - 10 weeks post-surgery between December 1998 and February 2005 as part of a randomized controlled trial of a stress management intervention. They were interviewed with the Hamilton Rating Scale for Depression (HRSD) and provided blood samples before initiating adjuvant chemotherapy or radiation. Participants in the sample for this thesis were those who had cryopreserved blood samples available for analysis of immune parameters (N= 59). They were predominately non-Hispanic white (72.9%), followed by Hispanic (20.3%) and Black (5.1%). Using linear regression, it was found that after controlling for age, stage, body mass index (BMI), time since surgery, and type of surgery (mastectomy versus lumpectomy), depression severity related to significantly greater levels of S100A8/A9 (p = .038), IL-1b (p = .011) and TNF-a (p = .026), and marginally with IL-6 levels (p = .062) at the post-surgical time point. Regression analyses indicated that S100A8/A9 served as an intermediary in the relationship between depression and circulating cytokines, demonstrating an indirect effect for IL-1β (effect = .058, 95% CI [.0009, .1687]) and IL-6 (effect = .064, 95% CI [.0070, .1685]) but not for TNF-α at the post-surgical time point. There was no significant relationship of pro-inflammatory cytokines or s100A8/A9 levels with depression at the one-year follow-up. An exploratory analysis indicated a similar pattern of results using affective and neurovegetative depressive symptom clusters at the post-surgical time point. Analyses revealed that depressive symptom clusters were not associated with S100A8/A9, IL-1b, IL-6 or TNF-a at the 12 month follow-up. These data suggest that depression may relate to greater inflammation in post-surgical breast cancer patients, and that the association between depression and pro-inflammatory cytokine levels may operate indirectly via activation of RAGE. The absence of these relationships at the 12-month follow-up suggests that other factors (e.g., recent adjuvant therapy regimen) may obscure associations between mood and inflammatory markers at this point in time. Because inflammatory processes may increase odds of metastasis, addressing depression early in the post-surgical period may have future health effects in breast cancer patients. However, the absence of these associations at the 12-month point suggests that these results need to be replicated in an independent sample.