Cognitive-Behavioral Stress Management Reverses
Anxiety-Related Leukocyte Transcriptional Dynamics
Michael H. Antoni, Susan K. Lutgendorf, Bonnie Blomberg, Charles S. Carver, Suzanne Lechner,
Alain Diaz, Jamie Stagl, Jesusa M.G. Arevalo, and Steven W. Cole
Background: Chronic threat and anxiety are associated with pro-inflammatory transcriptional profiles in circulating leukocytes, but the
intervention targeting negative affect and cognition might counteract anxiety-related transcriptional alterations in people confronting a
major medical threat.
Methods: One hundred ninety-nine women undergoing primary treatment of stage 0–III breast cancer were randomized to a 10-week
profiling and bioinformatic analyses at baseline, 6-month, and 12-month follow-ups.
Results: Baseline negative affect was associated with ?50% differential expression of 201 leukocyte transcripts, including upregulated
? time interaction), including downregulation of pro-inflammatory and metastasis-related genes and upregulation of type I interferon
response genes. Promoter-based bioinformatic analyses implicated decreased activity of NF-?B/Rel and GATA family transcription factors
Conclusions: In early-stage breast cancer patients, a 10-week CBSM intervention can reverse anxiety-related upregulation of pro-inflam-
can influence physical health and alter peripheral inflammatory processes that may reciprocally affect brain affective and cognitive
Key Words: Cancer, cognitive-behavioral stress management, gene
ing immune cells (1–4). Across a variety of different threat- and
anxiety-related experiences, such as imminent bereavement (5),
life adversity (9), and low socioeconomic status (10–12), genome-
er-based bioinformatic analyses have implicated several specific
transcription factors (TFs) as potential mediators of this transcrip-
tional shift, including activation of pro-inflammatory NF-?B/Rel-
family TFs (6,7,11) and GATA-family TFs (9), decreased activity of
esearch in social genomics has linked extended periods of
significant life adversity to alterations in the gene transcrip-
antagonize NF-?B/Rel factors and reduce inflammation (13). Sev-
eral studies suggest that adversity-related alterations in the circu-
experiences of threat or anxiety than they are to objective external
conditions such as social network density or socioeconomic status
The causal relationship between experienced threat or anxiety
existing analyses generally involve correlational study designs. Ex-
tentially induce experiences of anxiety, depression, or other nega-
tive affective states via cytokine effects on the brain (4,14–18).
However, experimental studies have also shown that negative af-
fective states can alter leukocyte gene expression via signals from
adrenal axis (2,4,19,20). In the present study, we sought to deter-
mine whether an experimental intervention that directly targets
anxiety-related cognitive and behavioral processes might re-
verse the pattern of leukocyte transcriptional alterations previ-
ously observed in people experiencing significant life adversity
Diagnosis with breast cancer generally evokes substantial
health-related anxiety, even among women with early-stage non-
women undergoing primary treatment for stage 0–III breast can-
cer, cognitive-behavioral stress management (CBSM) (24,25) has
been found to reduce anxiety-related symptoms and general neg-
studies, CBSM-induced psychological effects have also been asso-
ciated with peripheral physiologic alterations that may either in-
duce or reflect changes in gene expression, including changes in
From the Departments of Psychology (MHA, CSC, JS), Microbiology and
Immunology (BB, AD), and Psychiatry and Behavioral Sciences (SL),
University of Miami, Coral Gables; and Sylvester Comprehensive Can-
cer Center (MHA, BB, CSC, SL, AD), University of Miami Hospital and
Clinics, Miami, Florida; Department of Psychology (SKL) and Holden
Comprehensive Cancer Center (SKL), University of Iowa, Iowa City,
(SWC), Jonsson Comprehensive Cancer Center (SWC), and Norman
Address correspondence to Michael H. Antoni, Ph.D., University of Miami,
Department of Psychology, 5665 Ponce DeLeon Boulevard, Coral Ga-
bles, FL 33124-0751; E-mail: MAntoni@miami.edu.
Received May 29, 2011; revised Oct 4, 2011; accepted Oct 5, 2011.
BIOL PSYCHIATRY 2011;xx:xxx
© 2011 Society of Biological Psychiatry
type 1 viral load (31). Given the established effects of CBSM in
reducing negative affect and cognition and evidence linking
threat/anxiety-related negative affect to immunologic processes,
this study tested the hypothesis that CBSM might reverse previ-
ously observed anxiety-related transcriptional alterations in circu-
from CBSM-treated breast cancer patients would show reduced
expression of pro-inflammatory gene programs and enhanced ex-
patients (i.e., patterns opposite those previously linked to experi-
enced threat/anxiety) (4). We also tested whether those transcrip-
tional dynamics might be associated with reversal of the specific
to anxiety-related transcriptional alterations (i.e., increased activity
of NF-?B/Rel- and GATA-family TFs and decreased activity of IRFs
and the GR) (13,32).
Methods and Materials
CBSM Randomized Controlled Trial
(80% stage I–II) who were recruited 4 to 8 weeks after primary
surgery, but before initiation of adjuvant therapy, and randomized
to either 1) a 10-week CBSM intervention focusing on anxiety re-
duction, cognitive restructuring, and coping skills; or 2) an active
contact control condition, as previously described (25–27,29) (Na-
months, and 12 months postrandomization, 79 participants pro-
vided venous blood samples from which 3–10 ? 106peripheral
blood mononuclear cells (PBMC) were isolated as previously de-
scribed (29) and serum cortisol concentrations were measured by
vided as Figure S1 in Supplement 1). All research was approved by
the Institutional Review Board at the University of Miami.
Demographic, Tumor, and Treatment Characteristics
As previously described (25–27,29), participant age, annual
household income, and ethnicity were assessed by standard self-
report instruments, and tumor characteristics (stage, hormone re-
ceptor status, number of involved lymph nodes), cancer treatment
parameters (surgery type, elapsed time since surgery, radiation
therapy, radiation treatment within the 3 weeks before each study
visit, chemotherapy, chemotherapy treatment within 3 weeks be-
fore each study visit, hormone therapy), and other medical thera-
Negative and Positive Affect
Intervention effects on negative and positive affect were as-
sessed by subscales from the Affects Balance Scale (ABS) (33) with
psychometric properties in this sample previously reported (26,27)
and results summarized for the present analyses by a composite
affect balance score computed as the difference between positive
effects on time trajectories of ABS positive affect, negative affect,
control) ? 3 (time: baseline, 6-month, and 12-month follow-up)
PROC MIXED; SAS Institute, Cary, North Carolina) (34). Analyses
were conducted on an intent-to-treat basis, including all available
data (including observations for individuals missing data at other
follow-up time points).
Gene Expression Profiling and Bioinformatic Analysis
Detailed methods for gene expression profiling and bioinfor-
matic analysis are presented in Supplement 1. Briefly, RNA was
extracted from PBMC, quality assured for mass and integrity, and
subject to genome-wide transcriptional profiling using Illumina
Human HT-12 v3 Expression BeadChips (Illumina Inc., San Diego,
(7,9). Data are deposited as National Center for Biotechnology In-
sis of baseline data identified genes showing ?50% differential
expression across the general range of ABS composite scores
(i.e., ?2 SD relative to the mean value) after control for age, race
(white vs. nonwhite), and tumor stage, estrogen receptor (ER), and
progesterone receptor (PR) status. Subsequent primary analyses
identified longitudinal effects of CBSM on expression of each ana-
a repeated measure and controlling for individual differences in
age, race, tumor stage, ER status, PR status, treatment with chemo-
on an intent-to-treat basis using mixed effect linear models (34).
change over time (contrast: average of 6-month and 12-month
follow-ups ? baseline) were identified as differentially expressed
by specific transcription factors was inferred from TELiS (http://
www.telis.ucla.edu/) bioinformatic analysis of transcription factor-
binding motifs in gene promoters (38), using TRANSFAC (http://
weight matrices (39), as previously described (7,9). Analyses of GR
signaling controlled for concurrent serum cortisol concentrations
(7) to assess GR signal transduction efficiency above and beyond
the effects of CBSM in altering glucocorticoid ligand availability
(29). Ancillary analyses also controlled for prevalence of lympho-
cyte subsets as assessed by flow cytometry (29). Transcript origin
predominately mediating CBSM effects on the overall PBMC pool
Twelve transcripts identified as differentially expressed by mi-
or on average across both follow-ups were re-verified using quan-
detailed in Supplement 1. Selected genes identified by microarray
Patient characteristics and CBSM intervention effects on psy-
chological outcomes and cortisol levels have been previously re-
ported for this study (26,27,29). Briefly, in this sample of stage 0–III
breast cancer patients recruited after surgery but before the initia-
tion of adjuvant therapy, the 10-week CBSM intervention signifi-
cantly reduced general anxiety-related symptoms, negative affect,
affect (27); reduced circulating cortisol levels (29); and increased
stimulated production of interleukin 2 and interferon-? over a 12-
month follow-up in comparison with the active contact control
2 BIOL PSYCHIATRY 2011;xx:xxx
M.H. Antoni et al.
for an intensive immunologic substudy and provided sufficient
PBMC samples for genome-wide transcriptional profiling at base-
line and at 6-month and/or 12-month follow-ups (CBSM n ? 45,
control n ? 34; CONSORT diagram in Figure S1 in Supplement 1).
CBSM group participants were more likely to provide PBMC sam-
ples (48.9%) than were control group participants (31.8%, differ-
patients did not differ in demographic characteristics, tumor char-
acteristics, treatment parameters (surgery type, radiation, chemo-
therapy, hormone treatment), or baseline affective state (Table 1).
Peripheral blood mononuclear cell contributors were representa-
tributors (45%) than in the total sample (60%, difference p ? .043)
profile of affective change over time as previously reported for the
total study cohort (26,27) (group ? time interaction, p ? .0042),
with the CBSM-treated group showing increased positive affect
(linear time trend over 12 months: mean 6.8 ? standard error 2.36
ABS score units, p ? .0055), decreased negative affect (?8.22 ?
2.08, p ? .0003), and a net positive trend in composite affect bal-
ance scores (17.54 ? 4.12, p ? .0001), whereas control group par-
ticipants showed negligible change over time on each dimension
(positive affect: ?.16 ? 1.94, p ? .936; negative affect: ?4.64 ?
3.94, p ? .245; overall affect balance: 1.00 ? 3.62, p ? .784).
In analyses relating baseline affective state to PBMC gene ex-
pression, genome-wide transcriptional profiling identified 201
named human genes showing ?50% difference in expression
across the ?2 SD range of ABS composite scores at study entry
(Table S1 in Supplement 1). One hundred seventy-seven genes
were upregulated in association with negative affect, including
genes encoding pro-inflammatory cytokines (IL1A, IL1B, IL6, TNF),
the prostaglandin-synthesis enzyme COX2 (PTGS2), the oxidative
stress response factor superoxide dismutase 2 (SOD2), inflamma-
CCL20, CXCL9, CXCL10, CXCR6, CXCR7), and transcripts involved in
tissue remodeling and epithelial-mesenchymal transition (LMNA,
MMP9). Gene Ontology analyses confirmed that negative affect-
linked transcripts were disproportionately involved in pro-inflam-
matory cytokine function (GO:0006954; GO:0005125; both p ?
.0001) and wound healing (GO:0009611; p ? .0001).
pro-inflammatory transcriptional skew associated with significant
life adversity in this sample and previous studies (5,7,9,11,21), we
carried out Gene Ontology analyses of all 91 named human genes
that showed ?50% difference between CBSM versus control
groups in the magnitude of change in transcript abundance from
patient age, race, disease stage [0–III], hormone receptor status
[ER?/?, PR?/?) and treatment (chemotherapy, radiation, hor-
mone therapy); genes are listed in Table S2 in Supplement 1, with
additional cross-sectional differences at each follow-up time point
listed in Tables S3 and S4 in Supplement 1. Sixty-two transcripts
showed significantly greater downregulation in CBSM-treated pa-
tients relative to control subjects, including genes encoding pro-
inflammatory cytokines (IL1A, IL1B, IL6), the prostaglandin-synthe-
sis enzyme COX2 (PTGS2), inflammatory chemokines and their
receptors (CCL2, CCL3, CCL3L1, CCL3L3, CCL4L1, CCL4L2, CCL7,
CXCL1, CXCL2, CXCR7), and mediators of tissue remodeling and
Ontology analyses confirmed that CBSM-downregulated genes
were characterized by involvement in pro-inflammatory cytokine
activity (GO:0006954; GO:0005125; both p ? .0001) and wound
healing (GO:0009611; p ? .0001). Thirty-one (50%) of the total 62
than the ?1% overlap expected by chance; binomial p ? .0001).
Negative affect-related transcripts that were downregulated by
CBSM included pro-inflammatory cytokines (IL1A, IL1B, IL6), COX2
(PTGS2), chemokines and related receptors (CCL3, CCL7, CCL20,
CCL3L1, CCL4L2, CXCR7), and mediators of wound healing and epi-
thelial-mesenchymal transition (LMNA, MMP9).
Twenty-nine genes showed significantly greater upregulation
over time in CBSM-treated patients versus control patients, includ-
ing transcripts involved in type I interferon response (IFIT1, IFIT2,
ing (IFNG), and interferon signal transduction (STAT1, STAT2). Gene
Ontology analyses confirmed that the most prominent functional
characteristic of CBSM-upregulated genes involved their role in
Table 1. Characteristics of CBSM and Control Group Participants
Providing PBMC Samples for Gene Expression Profiling
(n ? 34)
(n ? 45)p
Surgery Type (%)
Days Postsurgery (at Study
Within 3 weeks of 6-month
Within 3 weeks of 12-month
Within 3 weeks of 6-month
Within 3 weeks of 12-month
Endocrine Therapy (%)
Affects Balance Scale (at Baseline)a
Affects Balance Scale (Linear
49.2 ? 7.8
80.3 ? 65.4
50.1 ? 7.5
72.8 ? 31.4
1.5 ? 3.4
.4 ? .2
41.6 ? 22.6
38.6 ? 21.6.561
31.2 ? 16.3
?1.0 ? 3.6
24.3 ? 22.2
?17.5 ? 4.1
CBSM, cognitive-behavioral stress management; ER, estrogen receptor;
PBMC, peripheral blood mononuclear cells; PR, progesterone receptor.
aMean ? SD.
M.H. Antoni et al.
BIOL PSYCHIATRY 2011;xx:xxx 3
antiviral responses (GO:0009615; p ? .0001). RT-PCR analysis con-
dance of 12 of 12 transcripts audited (average 69% difference in
expression, all p ? .0001; Table S5 in Supplement 1).
In CBSM dose-response analyses, only 4 of the 91 differentially
expressed genes (4.4%) showed changes in expression that were
proportional in magnitude to CBSM group attendance rates. How-
ever, CBSM attendance rates were generally high (mean 65.8% ?
ing 5 or more of the scheduled 10 sessions), limiting the range of
CBSM dose variation available to resolve dose dependence.
To determine whether CBSM-induced transcriptional altera-
tions might be structured by specific TFs previously implicated in
leukocyte transcriptional responses to threat and anxiety, we car-
ried out TELiS bioinformatic analyses of transcription factor-bind-
ing motif distributions within the promoters of differentially ex-
pressed genes. Promoters of CBSM-upregulated genes showed a
significant overrepresentation of DNA response elements for IRF
transcription factors and underrepresentation of response ele-
ments for NF-?B/Rel- and GATA-family TFs (Figure 1). Parallel anal-
levels showed an overrepresentation of GR response elements in
the promoters of CBSM-upregulated genes (Figure 1). Differential
transcription of genes bearing GR response elements was not
attributable to differential expression of the NR3C1 gene encod-
ing the GR, which showed no substantial variation in transcript
? 5%, all p ? .20).
Transcript origin analyses (8) identified monocytes and plasma-
cytoid dendritic cells (pDCs) as cellular contexts for CBSM-induced
predominately from monocytes (p ? .0128) and downregulated
transcripts associated with both monocytes (p ? .0001) and pDCs
(p ? .0008).
Ancillary analyses examined the possibility that CBSM-related
differences in the aggregate leukocyte transcriptome might stem
from redistribution of leukocyte subsets within the PBMC popula-
CD19? B lymphocytes, CD4? T lymphocytes, CD8? T lympho-
differences ? 5%, all p ? .20; no flow cytometry analyses of mono-
cyte or pDC prevalence were available), and controlling for varia-
tions in leukocyte subset prevalence continued to show CBSM-in-
tivation also continued to emerge in ancillary analyses that con-
trolled for additional treatment-related variables, including recent
study visit), primary surgery type (lumpectomy, mastectomy, or
or antidepressants (downregulation of pro-inflammatory genes,
GO:0006954; GO:0009611; both p ? .0001; upregulation of innate
antiviral response genes, GO:0009615; p ? .0001).
The results of this study link negative affective states to in-
uals confronting significant life adversity (5–8,10,11), and they
show that a CBSM intervention targeting anxiety-related affective
and behavioral processes can counteract that transcriptional bias
by reducing expression of pro-inflammatory and metastasis-re-
lated genes and increasing expression of interferon-related genes.
10-week CBSM intervention or an active contact control condition,
pression of genes encoding pro-inflammatory cytokines and in-
from a randomized intervention trial analyzed by intent-to-treat
and controlling for any potential confounding effects of patient
demographic, tumor, or treatment-related characteristics. These
CBSM-induced longitudinal transcriptional alterations provide the
first indication that psychological interventions can causally
change the basal leukocyte transcriptome, and they implicate
threat- and anxiety-related processes as potential central nervous
system (CNS) mediators of those effects (1,2). These transcriptional
alterations could have significant implications for both cancer-re-
Figure 1. Fold-difference in prevalence of transcription factor-binding mo-
factor-, NF-?B/Rel-, and GATA-family transcription factors within the pro-
moters of 29 genes found to be upregulated in peripheral blood mononu-
clear cells from CBSM-treated breast cancer patients relative to 62 genes
upregulated in active contact control subjects. V$ TFBM matrix names indi-
cate vertebrate TRANSFAC position-specific weight matrices used in each
analysis. CBSM, cognitive-behavioral stress management.
and downregulated in peripheral blood mononuclear cells from cognitive-
behavioral stress management-treated breast cancer patients. Data repre-
indicated cell type (8), with positive values indicating that differentially
expressed genes originate disproportionately from the analyzed cell type
4 BIOL PSYCHIATRY 2011;xx:xxx
M.H. Antoni et al.
lated disease processes (20) and psychological adaptation to the
significant threat and anxiety provoked by breast cancer diagnosis
and treatment (22,23).
The common pattern of pro-inflammatory transcriptional bias
observed in this study of breast cancer patients and previous stud-
(5–8,10,11) suggests that there may exist a conserved transcrip-
of diverse challenges to activate common psychological reactions
(e.g., threat/anxiety) and associated neural and endocrine re-
sponses (e.g., SNS and hypothalamic-pituitary-adrenal axis) that
ultimately modulate leukocyte gene expression (4). In several pre-
vious studies, pro-inflammatory alterations in the basal leukocyte
interferon-related genes (5,7,8,11). This study found no significant
interferon suppression associated with baseline negative affect,
but it did identify CBSM-induced upregulation of type I interferon-
lation of pro-inflammatory cytokines. Thus, experienced threat/
anxiety appears to shift the leukocyte basal transcriptional
favor of pro-inflammatory cytokines (4). It is unclear why the pro-
inflammatory transcriptional skew associated with negative affect
at baseline was not accompanied by a detectable suppression of
does generally exist but was not evident due to affective range
restriction at baseline (i.e., all participants confronted a significant
life adversity in recent breast cancer diagnosis, and thus few or
none may have experienced positive/nonanxious affect levels suf-
ficient to reveal associations with type I interferon signaling) and
only emerged after the CBSM intervention induced significant af-
fective differences by 6-month and 12-month follow-ups.
Three other features of these data are also consistent with the
from the reversal of a CNS-mediated CTRA. First, the genes down-
regulated by CBSM disproportionately included transcripts that
(enriched ? 100-fold relative to the overlap expected by chance).
Second, bioinformatic inferences of the specific cell types mediat-
ing CBSM transcriptional alterations implicated the same myeloid
lineage antigen presenting cells (monocytes and pDCs) linked to
tion and downregulation of distinct groups of monocyte-related
induced transcriptional alterations mirror those previously linked
family TFs have been linked to life adversity and SNS signaling
(5–7,9,11,21,43), and the present analyses suggest reductions in
their activity following CBSM. The present analyses also indicate
CBSM-induced activation of IRF-family TFs and the GR, both of
which are inhibited by SNS signaling (42,44) and were previou-
sly implicated in CTRA-related transcriptional downregulation
(5,7,9,11,21). CBSM increased the expression of genes bearing GR
response elements, despite the fact that circulating cortisol levels
were reduced in CBSM-treated patients relative to control subjects
(29). These effects also emerged despite statistical control for indi-
any differential expression of the NR3C1 gene encoding the GR.
Such findings are consistent with the hypothesis that CBSM affects
GR target gene expression primarily by enhancing GR functional
sensitivity (i.e., reversing threat-induced GR desensitization)
(5,11,32,45,46), with such stimulatory effects outweighing the si-
multaneous effects of reduced circulating GR ligand levels (29).
Although the present results are consistent with the theorized role
of these TFs in mediating the leukocyte CTRA and its reversal by
CBSM, it is important to note that the bioinformatic analyses pre-
sented here represent indirect inferences of TF activity based on
promoter sequence associations and cannot definitively establish
that these TFs are causally responsible for the observed transcrip-
Beyond demonstrating a general influence of cognitive/behav-
ioral processes on the basal transcriptional stance of circulating
immune cells in people confronting significant life threat (4), the
present results may have specific health implications for women
with breast cancer (20). CBSM- induced downregulation of pro-
indications of NF-?B/Rel activity are notable because chronic in-
flammation has been implicated in breast cancer progression and
genes known to play a role in cancer progression (e.g., those in-
volved in myeloid cell induction of the metastasis-promoting epi-
thelial-mesenchymal transition) (49), while enhancing expression
of type I interferon-related genes that are associated with reduced
ular framework for understanding both the general link between
psychological processes and cancer progression (20,24) and salu-
tary effects of cognitive-behavioral interventions on breast cancer
clinical disease progression (53,54).
kocyte gene expression profiles, but the scope of conclusions that
can be drawn from this study are limited in several important re-
spects. In addition to causal effects of cognitive-behavioral pro-
cesses on leukocyte transcriptional programs, pro-inflammatory
cytokines may also signal to the brain to causally affect neural
function (14–18), thus inducing a bi-directional regulatory circuit
mediated threat or anxiety processes (4,55). Several key gene tran-
scriptional dynamics identified in the present gene expression
sion and/or previous studies of protein expression (e.g., interfer-
tions within the tumor microenvironment (20). The clinical health
impact of the observed leukocyte transcriptional dynamics also
requires further definition (e.g., assessing effects on progression-
free or total survival times). However, the present molecular find-
ings are consistent with other recent studies documenting im-
proved survival and reduced disease recurrence in nonmetastatic
breast cancer patients randomized to a broadly similar cognitive-
behavioral intervention (53,54). Although these data document
longitudinal changes in leukocyte gene expression for 6 to 12
months after a 10-week CBSM intervention, the ultimate duration
of transcriptional impact remains to be established, as do other
potential limiting conditions. In particular, CBSM intervention ad-
herence rates were quite high in this study, and it is therefore
difficult to determine whether transcriptional effects are dose-de-
pendent on intervention magnitude/adherence. Finally, the pres-
breast cancer patients, and it is unclear whether similar results
would occur in other populations, disease settings, or types of life
This study demonstrates that a psychologically targeted inter-
vention delivered in the anxiety-provoking context of primary
M.H. Antoni et al.
BIOL PSYCHIATRY 2011;xx:xxx 5
breast cancer treatment can reverse some of the major changes in
immune system gene expression previously observed in people
confronting significant life adversity (1,2). These findings provide a
the process of mapping specific biological pathways by which
those dynamics might potentially alter the course of somatic dis-
eases such as breast cancer (56,57) and reciprocally feed back to
influence threat- and anxiety-related brain processes (4,15,55).
This research was supported by the National Institutes of Health
(AG010415, AG028748, AG107265, AI052737, CA116778, CA064710,
CA140933, DK082344), the Sylvester Comprehensive Cancer Center,
We gratefully acknowledge the patients who participated in this
Dr. Antoni reports receiving publication royalties from a book and
related training materials that he has authored on cognitive-behav-
ioral stress management treatments in health psychology. All other
authors reported no biomedical financial interests or potential con-
ClinicalTrials.gov: Facilitating Positive Adaptation to Breast Cancer;
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