Circadian disruption and biomarkers of tumor progression in breast cancer patients awaiting surgery.
Psychological distress, which can begin with cancer diagnosis and continue with treatment, is linked with circadian and endocrine disruption. In turn, circadian/endocrine factors are potent modulators of cancer progression. We hypothesized that circadian rest-activity rhythm disruption, distress, and diurnal cortisol rhythms would be associated with biomarkers of tumor progression in the peripheral blood of women awaiting breast cancer surgery. Breast cancer patients (n=43) provided actigraphic data on rest-activity rhythm, cancer-specific distress (IES, POMS), saliva samples for assessment of diurnal cortisol rhythm, cortisol awakening response (CAR), and diurnal mean. Ten potential markers of tumor progression were quantified in serum samples and grouped by exploratory factor analysis. Analyses yielded three factors, which appear to include biomarkers reflecting different aspects of tumor progression. Elevated factor scores indicate both high levels and strong clustering among serum signals. Factor 1 included VEGF, MMP-9, and TGF-β; suggesting tumor invasion/immunosuppression. Factor 2 included IL-1β, TNF-α, IL-6R, MCP-1; suggesting inflammation/chemotaxis. Factor 3 included IL-6, IL-12, IFN-γ; suggesting inflammation/TH1-type immunity. Hierarchical regressions adjusting age, stage and socioeconomic status examined associations of circadian, distress, and endocrine variables with these three factor scores. Patients with poor circadian coordination as measured by rest-activity rhythms had higher Factor 1 scores (R(2)=.160, p=.038). Patients with elevated CAR also had higher Factor 1 scores (R(2)=.293, p=.020). These relationships appeared to be driven largely by VEGF concentrations. Distress was not related to tumor-relevant biomarkers, and no other significant relationships emerged. Women with strong circadian activity rhythms showed less evidence of tumor promotion and/or progression as indicated by peripheral blood biomarkers. The study was not equipped to discern the cause of these associations. Circadian/endocrine aberrations may be a manifestation of systemic effects of aggressive tumors. Alternatively, these results raise the possibility that, among patients with active breast tumors, disruption of circadian activity rhythms and elevated CAR may facilitate tumor promotion and progression.
Department of Surgery, Division of Otolaryngology-HNS, University of Louisville School of Medicine, Louisville, KY, United States; Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.
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Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States. Electronic address: sephton@louisville.edu.
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Sephton
The Breast Center - Smilow Cancer Hospital at Yale-New Haven, Department of Surgery, Yale University School of Medicine, New Haven, CT, United States.
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Chagpar
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, United States.
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Spiegel
Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States.
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Rebholz
Department of Psychological & Brain Sciences, University of Louisville, Louisville, KY, United States.
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Zimmaro
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States.
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Tillie
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, United States; Institute for Immunity, Transplantation, and Infection, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, United States. Electronic address: dhabhar@gmail.com.
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Dhabhar
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood* / Q000473:pathology / Q000523:psychology; D002940:Circadian Rhythm / Q000502:physiology*; D016207:Cytokines / Q000097:blood*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008875:Middle Aged; D008962:Models, Theoretical; D013315:Stress, Psychological / Q000097:blood* / Q000473:pathology / Q000523:psychology; D055815:Young Adult
D015415:Biomarkers; D016207:Cytokines; D006854:Hydrocortisone
Angiogenesis; Biomarker; Breast cancer; Cortisol; Immunosuppression; Inflammation; Invasion; Metastasis; Rest–activity; Rhythms