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RESEARCH 

Psychosocial Stress, Glucocorticoid 
Signaling and Prostate Cancer Health 
Disparities in African American Men 
Leanne Woods-Burnham1,#, Laura Stiel2, Shannalee R. Martinez1, Evelyn S. Sanchez-Hernandez1, Herbert C. 
Ruckle3, Frankis G. Almaguel1,4, Mariana C. Stern5, Lisa R. Roberts6, David R. Williams7, Susanne 
Montgomery1,,2, Carlos A. Casiano1.8* 

1Center for Health Disparities and Molecular Medicine and Department of Basic Sciences, Loma Linda University 
School of Medicine, Loma Linda, CA, USA; 2Loma Linda University School of Behavioral Health, Loma Linda, CA, USA; 
3Department of Surgical Urology, Loma Linda University School of Medicine, Loma Linda, CA, USA; 4Loma Linda 
University Cancer Center, Loma Linda, CA, USA; 5Departments of Preventive Medicine and Urology, University of 
Southern California Keck School of Medicine, Los Angeles, CA; 6Loma Linda University School of Nursing, Loma 
Linda, CA, USA; 7Department of Social and Behavioral Sciences, Harvard University School of Public Health; 
8Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA. 
#Current Address: City of Hope Comprehensive Cancer Center, Department of Population Sciences, Division of 
Health Equities, 1500 East Duarte Rd, Duarte CA 91010 
 
*Corresponding author: Carlos A. Casiano, Email: ccasiano@llu.edu. 

ABSTRACT: Recent advances in our understanding of racial disparities in prostate cancer (PCa) 
incidence and mortality that disproportionately affect African American (AA) men have provided 
important insights into the psychosocial, socioeconomic, environmental, and molecular contributors. 
There is, however, limited mechanistic knowledge of how the interplay between these determinants 
influences prostate tumor aggressiveness in AA men and other men of African ancestry. Growing 
evidence indicates that chronic psychosocial stress in AA populations leads to sustained 
glucocorticoid signaling through the glucocorticoid receptor (GR), with negative physiological and 
pathological consequences. Compelling evidence indicates that treatment of castration-resistant 
prostate cancer (CRPC) with anti-androgen therapy activates GR signaling. This enhanced GR 
signaling bypasses androgen receptor (AR) signaling and transcriptionally activates both AR-target 
genes and GR-target genes, resulting in increased prostate tumor resistance to anti-androgen 
therapy, chemotherapy, and radiotherapy. Given its enhanced signaling in AA men, GR—together 
with specific genetic drivers—may promote CRPC progression and exacerbate tumor aggressiveness 
in this population, potentially contributing to PCa mortality disparities. Ongoing and future CRPC 
clinical trials that combine standard of care therapies with GR modulators should assess racial 
differences in therapy response and clinical outcomes in order to improve PCa health disparities that 
continue to exist for AA men. 
KEYWORDS: African American, African ancestry, clinical trials, glucocorticoid receptor, glucocorticoid 
signaling, health disparities, prostate cancer, psychosocial stress  

Citation: Woods-Burnham L et al (2020) Psychosocial Stress, Glucocorticoid Signaling, and Prostate Cancer 
Health Disparities in African American Men. Cancer Health Disparities 4:e1-e30. doi:10.9777/chd.2020.1005.



 
 
 
 
 

 
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Introduction 

Prostate cancer (PCa) is the most commonly 
diagnosed cancer and the second leading cause of 
cancer mortality in men in the United States (U.S.) 
(Siegel et al., 2020). Approximately 191,930 men 
will be diagnosed with PCa and 33,330 will die 
from this malignancy in the U.S. in 2020 (Siegel et 
al., 2020). African-American (AA) men have the 
highest rates of PCa incidence and mortality 
compared to men of other races and ethnicities in 
the U.S. (Siegel et al., 2020). These disparities have 
also been reported in other populations of men 
with African ancestry (Petersen et al., 2019; 
Rebbeck, 2017). At time of diagnosis, AA men and 
African men show a greater frequency of high-risk 
prostate tumors compared to men from other 
racial groups, ultimately resulting in increased 
mortality (Cuevas et al., 2019; Petersen et al., 2019; 
Rebbeck, 2017; Woods-Burnham et al., 2018a). 
Emerging evidence supports the notion that these 
disparities stem from the interplay between 
multiple factors including socioeconomic status 
(SES), environment, and biology (Abdalla et al., 
1999; Chornokur et al., 2011; DeSantis et al., 2019; 
Moul et al., 1995). 

An emerging area in the field of PCa health 
disparities research is the contribution of 
psychosocial stress or socioenvironmental 
adversity to an increased risk of tumor 
aggressiveness, particularly in AA men (Cuevas et 
al., 2019; Kantor et al., 2019; Woods-Burnham et 
al., 2018a). In this review we discuss recent studies 
linking psychosocial stress with increased 
glucocorticoid signaling in AA populations. We 
also discuss emerging evidence pointing to 
glucocorticoid signaling through the 
glucocorticoid receptor (GR) as critical for PCa 
progression into the therapy-resistant advanced 
stage. We propose a model (Fig. 1) that integrates 
psychosocial stress, glucocorticoid signaling, and 
PCa progression in the context of PCa health 
disparities. In this model, cumulative exposure to 
psychosocial stressors (e.g. discrimination, 
negative neighborhood effects, low SES, limited 
access to health care) contributes to sustained 
elevated levels of cortisol resulting in amplified GR 
signaling. This amplified GR signaling is further 
increased by anti-androgen therapy during PCa 
treatment, leading to the activation of molecular 
mechanisms associated with PCa aggressiveness 
and therapy resistance. 

 



 
 
 
 
 

 
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Fig. 1 Psychosocial stress, glucocorticoid signaling, and prostate cancer progression in the context of 
health disparities. Chronic or cumulative exposure of AA men to psychosocial stressors (e.g. discrimination, 
negative neighborhood effects, low SES, limited access to health care) contributes to sustained elevated 
levels of cortisol resulting in amplified GR signaling leading to the activation of molecular mechanisms 
associated with prostate tumor aggressiveness and therapy resistance. AA, African American; GR, 
glucocorticoid receptor; SES, socioeconomic status. 

Prostate cancer health disparities 
AA men are more likely to be diagnosed and die 
from PCa than European American (EA) men 
(Siegel et al., 2020). While it is estimated that 1 in 9 
EA men will be diagnosed with PCa in their 
lifetime, the estimation rate in AA men is 1 in 7 
(DeSantis et al., 2019). We recently reported that 1 
in 3 AA men had elevated circulating PSA in a 
random sample of 414 adult AA men from the 
community (Woods-Burnham et al., 2018b). The 
biological characteristics of prostate tumors are 
exaggerated in AA men compared to EA men at 
time of diagnosis, including higher PSA levels, 
higher Gleason scores, differential anatomical 
localization of the tumors, and advanced tumor 
stage (Abdalla et al., 1999; Chornokur et al., 2011; 
Moul et al., 1995). Moreover, AA men show a 
higher rate of errors at the time of biopsy, leading 
to under-detection of higher grade disease at the 
time of diagnosis, which may compromise their 
outcomes (Sanchez-Ortiz et al., 2006; Sundi et al., 
2013). 

Multifactorial causes of PCa health disparities. The 
causes of these racial disparities are complex and 
include the interplay between multiple factors such 
as SES, biological and genetic determinants, stress, 
diet, lifestyle, and access to healthcare (DeRouen 
et al., 2018; DeSantis et al., 2019; Deshmukh et al., 
2017; Kelly et al., 2017; Kinlock et al., 2016; Krok-
Schoen et al., 2017; Mahal et al., 2017; Singh and 
Jemal, 2017; Tsodikov et al., 2017; Weprin et al., 
2019). Low SES directly affects diet, lifestyle, and 

access to healthcare, and therefore contributes 
significantly to cancer health disparities (Bach et 
al., 2002; Benjamins et al., 2016; DeSantis et al., 
2019; Ward et al., 2004). AAs have been reported 
to suffer disparities for many cancer risk factors, 
such as lower dietary quality, greater rates of 
obesity, lower rates of physical activity, higher 
rates of exposure to endocrine disruptive 
chemicals, and higher prevalence of night-shift 
work (Wang and Chen, 2011). 

Income inequalities also contribute to increased 
exposure to risk factors such as barriers to high-
quality cancer prevention, early detection, and 
cutting-edge treatment options (Bach et al., 2002; 
Benjamins et al., 2016; DeSantis et al., 2019; Ward 
et al., 2004). The level of education affects 
potential income, and AAs have lower percentages 
of college degrees and higher rates of poverty 
than EAs (DeSantis et al., 2019). Less education 
leading to lower income also affects neighborhood 
placement, and low SES neighborhoods are more 
likely to be targeted by marketing that promotes 
behaviors known to increase cancer risk (DeSantis 
et al., 2016). Lower SES also translates to worse 
overall cancer survival rates for several reasons 
that include limited access to high-quality health 
care (Bach et al., 2002; Shavers and Brown, 2002; 
Ward et al., 2008; Zeng et al., 2015). 

Worse overall survival is also influenced by the fact 
that AAs are more likely to be diagnosed with PCa 
at advanced tumor stage, which limits treatment 
options and reduces their efficacy (Arace et al., 



 
 
 
 
 

 
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RESEARCH 

2020; DeSantis et al., 2016). AA men also 
experience lower PCa screening rates compared to 
non-AA men (Misra-Hebert et al., 2017). We 
recently reported that in a sample of 264 AA/Black 
men over 45 years old living in the U.S. who met 
the American Cancer Society criteria for screening, 
only 49.6% had ever been screened and only 
29.2% had a PSA test within the last year, 
consistent with other reports of lower rates of 
screening among AA men (Roberts et al., 2018). In 
another study of 414 AA/Black men (mean age 
48.9 years) living in the U.S., we found that less 
than half (45.2%) of the participants had discussed 
PCa screening with their physicians, and detected 
higher-than-normal PSA values in 29.1% of the 
men who had not discussed PCa screening 
(Woods-Burnham et al., 2018b). 

Even when provided the same PCa treatment as 
EA men, AA men are more likely to experience 
delay in treatment administration and suffer 
greater postoperative complications (Schmid et al., 
2016). In addition, AAs are less likely to enroll in 
clinical trials, preventing them from exposure to 
cutting-edge treatment options (Murthy et al., 
2004; Wallace et al., 2011). Co-morbidities affecting 
delivery of optimal treatment, including obesity, 
diabetes, and hypertension, are higher in AAs and 
may exacerbate PCa mortality (Braithwaite et al., 
2009; Tammemagi et al., 2005; Yancik et al., 1998). 
The current COVID-19 pandemic has clearly 
exposed how these co-morbidities, combined with 
an adverse and stressful host-environment, have 
rendered AA populations more vulnerable during 
the pandemic (Holmes et al., 2020). 

Molecular determinants of prostate cancer 
disparities. Although studies from the U.S. Veteran 
Administration health care system suggest that 
PCa health disparities can be attenuated with 

better access to health care (Daskivich et al., 2015; 
Riviere et al., 2020), other studies indicate that 
these disparities persist even after controlling for 
SES, clinical setting, and access to care (Du et al., 
2011; Kish et al., 2014; Nettey et al., 2018). This 
suggests that molecular or biological determinants 
may also contribute to these disparities (Bhardwaj 
et al., 2017; Singh et al., 2017). Genomic differences 
between AA and EA men with PCa hint that 
genetic mediators may drive PCa health disparities 
(Batai et al., 2016; Gusev et al., 2016; Han et al., 
2015; Hoffman et al., 2001; Powell et al., 2013; Rand 
et al., 2016; Reams et al., 2009; Wallace et al., 
2008; Wang et al., 2017). This is supported by the 
identification of PCa susceptibility loci for AA men 
in both linkage studies and genome-wide 
association studies (GWAS) (Gudmundsson et al., 
2007; Kote-Jarai et al., 2011; Yeager et al., 2007). 
Interestingly, genetic variation on the chromosome 
8q24 region, where the c-MYC gene is located, 
has been consistently associated with PCa risk, and 
ethnic specific mutations and haplotypes have 
been reported in African populations (Chung et al., 
2014; Darst et al., 2020). 

In addition to inherited genomic factors linked to 
PCa, there are also genetic alterations that are 
associated with PCa risk (Rebbeck, 2017). Recent 
genomic studies on human prostate tumors have 
identified multiple oncogenic drivers of PCa 
development. These include chromosomal 
translocations resulting in the generation of a 
fusion between the TMPRSS2 (a transmembrane 
serine protease) and ERG (a member of the ETS 
transcription factor family) genes, as well as 
mutations or alterations in genes associated with 
phosphoinositide 3-kinase(PI3K)-AKT signaling, 
WNT/β-catenin pathway, transcription and 
epigenetic regulation (e.g. ETS, FOXA1, KMT2C/D, 
SWI/SNF complex members), ubiquitination (e.g. 



 
 
 
 
 

 
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SPOP and CUL3), DNA repair (e.g. BRCA2, ATM, 
CDK12), tumor suppression (e.g. TP53, PTEN), RAS-
MAPK signaling, and AR signaling (Armenia et al., 
2018; Banerjee et al., 2018; Frank et al., 2018; 
Warner et al., 2019). The frequencies of mutations 
and alterations in these genetic drivers vary 
according to disease stage. 

The TMPRSS2:ERG fusion has been found at lower 
frequencies in AA men (∼28%) and Black men 
from Africa (∼13%), compared to EA men (49%) 
(Blackburn et al., 2019). AA and EA men also have 
significant differences in ERG expression (Yamoah 
et al., 2015). The prognostic values of 
TMPRSS2:ERG fusion and ERG expression are not 
clear, but the relationship with PCa risk factors 
differs by TMPRSS2:ERG translocation status 
(Ahearn et al., 2016; Netto, 2013). In addition, the 
association between obesity and worse PCa 
outcome has been found in men harboring the 
TMPRSS2:ERG (Pettersson et al., 2013). By default, 
AA men, who have greater rates of obesity than 
EA men (Rebbeck, 2017), harboring the 
TMPRSS2:ERG translocation may have a poorer 
PCa prognosis than EA men. Interestingly, exome 
and whole-genome sequencing of AA prostate 
tumors revealed loss of function mutations in ERF, 
an ETS transcriptional repressor, lower frequency 
of ERG fusions, PIK3CA mutations and PTEN 
deletions, as well as increased frequency of SPOP 
mutations and expression of long non-coding 
RNAs (lncRNAs), compared to EA PCa (Huang et 
al., 2017; Jaratlerdsiri et al., 2018; Yuan et al., 2020). 
Another recent study showed that TP53 mutations, 
mutations in the DNA repair gene BRCA2, and 
deletions in CDKN1B (cyclin-dependent kinase 
inhibitor B1) are associated with increased risk of 
metastasis among AA men with PCa (Petrovics et 
al., 2019). However, another study showed that 
alterations in DNA repair genes, including BRCA1/2 

and ATM, are less likely to be detected in AA 
patients with PCa compared to EA patients (Sartor 
et al., 2020). 

Gene expression profiling of PCa tumors have also 
revealed differences in tumor immunobiology 
between AA and EA men (Wallace et al., 2008). 
For instance, genes associated with autoimmunity 
and inflammation, particularly those clustering in 
immune response, stress response, cytokine 
signaling, and chemotaxis pathways are 
differentially upregulated in AA prostate tumors 
(Wallace et al., 2008). A recent study that 
integrated the genomic and transcriptomic 
landscape between AA PCa and EA PCa revealed 
an enrichment of highly expressed differentially 
expressed genes (DEGs) for immune-related 
pathways in AA men, compared to increased 
enrichment for PTEN/PI3K signaling in EA men 
(Yuan et al., 2020). Metastasis-promoting genes 
are also more highly expressed in AA prostate 
tumors, including autocrine mobility factor 
receptor, chemokine receptor 4, and matrix 
metalloproteinase 9 (Wallace et al., 2008). 
Inflammation associated genes such as IL6, IL8, 
IL1B, CXCR4, and FASN were also found to be 
significantly expressed at higher levels in prostate 
tumors from AA compared to EA men (Powell et 
al., 2013). The expression of many of these genes 
have been associated with diet and lifestyle, higher 
Gleason scores, androgen receptor (AR) signaling, 
aggressive PCa tumors, and metastasis (Dubrovska 
et al., 2012; Finley et al., 2009; Jia et al., 2004; 
Nguyen et al., 2010; Powell et al., 2013; Yang et al., 
2004). Consistent with the notion of differential 
expression of immune function-related genes 
between AA and EA men with PCa, our group 
reported race-related differences in serum 
autoantibody responses to specific tumor-



 
 
 
 
 

 
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associated antigens in PCa patients (Sanchez et al., 
2016). 

The RNA splicing landscape has also been 
explored as a potential biological determinant of 
PCa health disparities (Olender and Lee, 2019; 
Wang et al., 2017). A genome-wide analysis of 
differential splicing (DS) events in racially diverse 
prostate tumors revealed hundreds of DS events 
that were unique to AA PCa and affected specific 
splice variants of several oncogenes such as 
PIK3CD, FGFR3, TSC2, and RASGRP2 (Olender and 
Lee, 2019). Validation studies showed that ectopic 
overexpression of a short splice variant of PIK3CD, 
enriched in AA tumors, enhanced the aggressive 
properties of PCa cells compared to the 
corresponding variant enriched in EA tumors. 
These results suggested that differential RNA 
splicing may contribute to increased tumor 
aggressiveness in AA PCa and could be exploited 
for developmental therapeutics in aggressive PCa. 

Given that androgens drive PCa etiology and 
disease progression prior to metastatic CRPC 
(mCRPC), several studies have also explored racial 
differences in androgen production and AR 
signaling (Bosland and Mahmoud, 2011; Karakas et 
al., 2017; Massengill et al., 2003; Schatzl et al., 
2003). These studies have shown that AA men 
have higher testosterone and active 5-alpha 
reductase levels than EA men, resulting in 
enhanced conversion of testosterone to the more 
potent DHT (Kheirandish and Chinegwundoh, 2011; 
Ross et al., 1992). The differential expression of 
epithelial and stromal AR in PCa tissue is also 
emerging as a possible driver of castration 
resistance in patients receiving ADT (Karakas et al., 
2017), and there is evidence that while nuclear AR 
levels are increased in AA PCa patients compared 
to EA patients, stromal levels are decreased (Li et 

al., 2008; Singh et al., 2014). In addition, AA PCa 
patients have higher frequency of germline and 
somatic AR mutations and their tumors show 
increased expression of specific AR target genes 
associated with tumor aggressive properties 
compared to those of EA PCa men (Gaston et al., 
2003; Jemal et al., 2006; Karakas et al., 2017). 

African Americans and psychosocial stress 
AAs are exposed to more cumulative lifetime 
stressors than other racial/ethnic groups, which 
detrimentally alters psychological and physical 
health (Cohen et al., 2006; Young et al., 1991; 
Zannas et al., 2015). The elevated levels of stress 
among AAs can be due, among other factors, to 
social isolation, racial discrimination, perceived 
discrimination, and segregation (Cacioppo and 
Hawkley, 2003; Cuevas et al., 2019; Williams and 
Collins, 2001). Chronic stress leading to 
dysregulation of endogenous cortisol production 
via the hypothalamic-pituitary-adrenocortical 
(HPA) axis can enhance risk for metabolic 
disorders and cancer (Cohen et al., 2006; Steptoe 
et al., 2000; Vedhara et al., 1999; Zannas et al., 
2015). As illustrated in Fig. 2, when the HPA axis is 
activated, neurons in the paraventricular nucleus 
of the hypothalamus are triggered to release 
corticotropin-releasing hormone (CRH) and 
arginine vasopressin, which stimulate the 
production and secretion of adrenocorticotropic 
hormone (ACTH) from the anterior pituitary gland, 
resulting in the synthesis and secretion of the 
steroid hormone cortisol, an endogenous 
glucocorticoid, from the adrenal cortex (Joseph 
and Whirledge, 2017; Stephens and Wand, 2012). 
A classical endocrine negative feedback loop 
inhibits further release of CRH and ACTH in 
response to rising levels of cortisol, thus 
maintaining a physiological homeostasis under 
normal conditions (Joseph and Whirledge, 2017). 



 
 
 
 
 

 
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In addition, the HPA axis tightly regulates glucose 
metabolism, cardiovascular function, cell 
proliferation and survival, growth, cognition and 
behavior, immune function, and reproduction 
directly through cortisol production (Joseph and 
Whirledge, 2017). Cortisol is secreted diurnally, 

peaking early in the morning when blood glucose 
levels are at the lowest and tapering throughout 
the day (Cohen et al., 2006). This diurnal rhythm is 
altered in response to chronically stressful 
situations (Adam and Gunnar, 2001; Cohen et al., 
2006). 

 

Fig. 2.  Physiological response to stress. Cortisol is secreted from the adrenal cortex in response to acute 
stress. A classical endocrine negative feedback loop inhibits further release of CRH and ACTH in response 
to rising levels of cortisol to maintain a physiological homeostasis under normal conditions. Chronic stress 
leading to dysregulation of endogenous cortisol production via the HPA axis can enhance risk for 
metabolic disorders and cancer. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing 
hormone; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenocortical. 

Chronic exposure to stressors is increased in 
individuals of low SES, and there is a positive 
association between low SES and stress in AA men 
(Cohen et al., 2006; Williams, 2003). Low SES is 
defined by lower income, education, or 
occupational status, and often results in increased 
exposure to environmental stressors leading to 
stress-related dysregulation of physiological 
systems and increased risk for disease (Adler et al., 
1994; Cohen et al., 2006; McEwen, 1998). However, 
even in AAs who have high SES, racial disparities in 
health persist, suggesting that there are alternative 

sources of stress other than SES (Farmer and 
Ferraro, 2005). For example, a poor lipid profile 
characterized by high triglycerides, LDL 
cholesterol, and total cholesterol, as well as lower 
HDL cholesterol, actually increases in AAs as 
education increases (Knox et al., 1996). 

National data reveals that strikingly high levels of 
racial inequality in SES exist in the U.S., having 
changed little over time, and that AAs continue to 
suffer from disproportionately lower SES (Williams 
et al., 2010), which has been shown to influence 
emotions and behaviors that alter cortisol levels 



 
 
 
 
 

 
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(Adler et al., 1994). Lower SES is also associated 
with greater perceived stress, depressive 
symptoms, negative affect, weak social networks 
and support, and sleep deprivation (Cohen et al., 
2006), factors linked to greater cortisol responses 
(Leproult et al., 1997; Polk et al., 2005; Pruessner et 
al., 2003; Seeman et al., 2001). However, whether 
lower SES by itself is associated with increased 
cortisol responses among AAs remains to be 
unambiguously established. A major study by 
Cohen and colleagues explored whether SES-
associated dysregulation of cortisol diurnal rhythm 
is independent of race and occurs equally in AAs 
and EAs (Cohen et al., 2006). This study reported 
that both lower SES (education and income) and 
being Black were associated with higher evening 
levels of cortisol (Cohen et al., 2006). These higher 
cortisol levels in AAs were associated with poorer 
health practices (e.g. smoking), higher levels of 
depressive symptoms, poorer social networks and 
supports, and feelings of helplessness (Cohen et 
al., 2006). This dysregulation has negative long-
term repercussions for the health of AAs (Williams 
et al., 2010; Williams and Sternthal, 2010; Zannas et 
al., 2015). 

Employed AAs are also more likely to be exposed 
to carcinogens and occupational hazards 
compared to other racial groups with matched 
education and job experience (Kaufman et al., 
1997; Williams and Sternthal, 2010). Compounding 
these realities, AAs have less purchasing power, as 
the costs of goods and services are highest in 
predominantly AA communities (Kaufman et al., 
1997; Williams and Sternthal, 2010). Outside the 
workplace, AAs are exposed to daily stressors 
within neighborhoods that are highly segregated 
(Williams et al., 2010), the effects of which 
negatively impact the SES and health of AA 
residents (Schulz et al., 2002; Williams and Collins, 

2001). For instance, optimal health is jeopardized 
in economically-disadvantaged, segregated 
neighborhoods as nutrition suffers in the presence 
of higher cost, lower quality, and decreased 
availability of healthy foods (Schulz et al., 2002; 
Williams and Collins, 2001). Similarly, physical 
activity is reduced in the absence of suitable 
recreational facilities amid safety concerns (Schulz 
et al., 2002; Williams and Collins, 2001). Exposure 
to environmental toxins and poor-quality living 
conditions also exist in neighborhoods 
accustomed to institutional neglect and 
disinvestment (Schulz et al., 2002; Williams and 
Collins, 2001). Adding to these cumulative stressful 
events are frequent experiences of discrimination 
and incarceration among AAs, which are 
associated with psychological distress and adverse 
physical health effects, including high incidence of 
chronic conditions such as hypertension, obesity, 
diabetes, substance abuse, and cancer (Byrd, 2012; 
Krieger et al., 2011). 

Combined, these stressors are directly linked to 
elevated risk of illness and death among AAs, and 
greatly contribute to existing racial disparities in 
health (Acevedo-Garcia et al., 2003; Williams and 
Collins, 2001). For example, AA men ages 57-85 
may have worse metabolic outcomes than their EA 
counterparts due to chronic inflammation arising 
from cumulative, multi-dimensional stress 
experienced over their lives (Das, 2013). 
Interestingly, a study based in Argentina of men 
ages 45-70 reported that uncontrollable stressful 
life events were inversely correlated with PSA 
among men with low cortisol, but positively 
correlated with PSA among men with high cortisol, 
suggesting that such events may be related to 
prostatic tumorigenic processes in men with high 
cortisol (Gidron et al., 2011). 



 
 
 
 
 

 
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Glucocorticoid receptor signaling 
GR biology. The cellular and pharmacological 
actions of cortisol and other glucocorticoids are 
mediated by GR, although low levels of 
glucocorticoids can also stimulate the 
mineralocorticoid receptor (MR) (Gomez-Sanchez 
and Gomez-Sanchez, 2014; Joseph and Whirledge, 
2017). GR is ubiquitously expressed throughout the 
human body, and signaling through this receptor 
regulates metabolism, growth, development, 
cardiovascular homeostasis, and cognition (Biddie 
et al., 2012; Oakley and Cidlowski, 2013). Synthetic 
glucocorticoids such as prednisone and 
dexamethasone have long been integral 
components of treatment regimens for 
inflammatory and autoimmune diseases as well as 
certain cancers (Vandewalle et al., 2018). As a 
member of the nuclear receptor family (which also 
includes receptors for estrogen, progesterone, and 
androgen), GR has both genomic (regulating gene 
transcription by binding to glucocorticoid 
response elements, GREs, in promoter regions) 
and non-genomic (modulating the function of 
intracellular kinases, including c-Src) effects 
(Oakley and Cidlowski, 2013). 

In the absence of ligand binding, GR resides in the 
cytoplasm as part of a large multi-protein complex 
including chaperone heat shock proteins hsp90, 
hsp70, and p23 as well as immunophilins of the 
FK506 family including FK506-binding protein 
(FKBP) 51 and FKBP52 (Grad and Picard, 2007; 
Joseph and Whirledge, 2017; Pratt and Toft, 1997). 
Upon ligand binding, a conformational change 
occurs releasing GR from the chaperone proteins 
and promoting its translocation into the nucleus 
where it exerts transcriptional regulation functions 
(Joseph and Whirledge, 2017). This nuclear 
translocation is promoted by signaling through the 
semaphorins Sema4D/Sema3C upon binding to 

their receptor PlexinB1 (Williamson et al., 2019). 
GR-mediated transcriptional control also extends 
to sequestration of other transcription factors 
(including NFkB and AP-1) to inhibit pro-
inflammatory gene expression as well as tethering 
transcription factors to facilitate gene transcription 
(Oakley and Cidlowski, 2011; Vandevyver et al., 
2014). 

While most cells express GR, its genetic structure is 
highly complex, and tissue-specific control of GR 
signaling is conferred, to a large extent, by the 
type and level of GR expressed (Ito et al., 2006). 
The gene encoding GR, NR3C1 (nuclear receptor 
subfamily 3 group C member 1), is composed of 9 
exons; however, the major transcriptional start site 
is within exon 2 and only exons 2 through 9 
encode protein (Ito et al., 2006; Vandevyver et al., 
2014). Exon 2 encodes the amino (N)-terminal 
modulatory domain, exons 3 and 4 encode the 
DNA-binding domain, exon 5 codes for a hinge 
region, and exons 6-9 encode the carboxy (C)-
terminal ligand binding domain (Kadmiel and 
Cidlowski, 2013). The 13 currently-identified 
variants of exon 1, with 9 possible promoter 
regions, form the 5’-untranslated region (UTR) and 
are thought to confer tissue specificity of GR 
expression (Turner and Muller, 2005). 

Alternative splicing of GR mRNA yields GRα, GRβ, 
GRγ, GR-A, and GR-P. GRα is expressed at higher 
levels in most cells, including cancer cells, than the 
other GR forms (Biddie et al., 2012; Vandevyver et 
al., 2014). GRβ is a closely-related variant to GRα, 
differing by ~35 amino acids within the ligand 
binding domain (Fig. 3). In contrast to GRα, GRβ 
does not bind glucocorticoids and is constitutively 
located in the nucleus (Biddie et al., 2012; Kassel 
and Herrlich, 2007; Mata-Greenwood et al., 2015). 
Although it does not directly mediate transcription, 



 
 
 
 
 

 
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GRβ has been shown to regulate gene expression 
through dominant-negative effects on GRα via 
heterodimer formation and also by epigenetically 
modifying chromatin structure through 
interactions with histone deacetylases (Nicolaides 
et al., 2010; Oakley and Cidlowski, 2013). GRγ, 
which makes up about 10% of total GR expression 
in most cells, is formed through alternative splicing 
between exons 3 and 4, with the incorporation of 
a single additional arginine nucleotide into the 
DNA binding domain (Morgan et al., 2016). This 
minor structural difference, while not affecting 
DNA binding affinity or total GR occupancy of 
target genes, still confers different sequence 
specificity and target gene control (through 
variable allosteric signal interpretation) compared 
to GRα (Morgan et al., 2016). Other notable 
aspects of GRγ are a delayed ligand-induced 
nuclear import (unlike beta, resides in the 
cytoplasmic region) as well as a pro-cellular 
respiration function within mitochondria (Morgan 
et al., 2016). The GR-A and GR-P isoforms are 
formed through removal of large portions of the 
ligand binding domain (exons 5-7 and exons 8-9, 
respectively)  (Oakley and Cidlowski, 2013). 
Comparatively less is known concerning these 
isoforms, but evidence suggests a ligand-
independent ability to modulate GRα function 
(Oakley and Cidlowski, 2013; Vandevyver et al., 
2014). 

A further layer of complexity in GR expression is 
introduced by 8 alternate translation initiation sites 
within exon 2, yielding a number of additional 
isoforms (Oakley and Cidlowski, 2013; Vandevyver 
et al., 2014). These have been identified for GRα 
and are predicted to exist for each of the other 
splice variants GRβ, GRγ, GR-A, and GR-P (Oakley 
and Cidlowski, 2013; Vandevyver et al., 2014). 
Furthermore, post-translational modifications of 

GR also regulate the receptor’s function in target 
cells (Vandevyver et al., 2014). Kinase activity 
(including MAPK, CDK, CK2, GSK-3β) at serine 
residues within the N-terminal domain occurs 
following glucocorticoid exposure (Oakley and 
Cidlowski, 2013; Vandevyver et al., 2014). These 
phosphorylation events may result in cytoplasmic 
sequestration (Ser-203, -226, -404), degradation, 
or enhanced transcriptional activity (-211) (Oakley 
and Cidlowski, 2013; Vandevyver et al., 2014). 
Other GR modifications include the addition of a 
ubiquitin moiety at lysine 419, which targets GR for 
proteasomal degradation; sumoylation of lysines 
277, 293, and 703, which modulate GR interactions 
with transcriptional co-regulators; and acetylation 
of lysines 494 and 495, which inhibit GR binding 
(and suppression) to NFkB, thus regulating GR’s 
anti-inflammatory function (Oakley and Cidlowski, 
2013; Vandevyver et al., 2014). 

In addition to modulating the level and form of GR 
expression, cells and tissues may also regulate 
immediate ligand availability (Oakley and 
Cidlowski, 2013). At the cellular level, the enzyme 
11β-hydroxysteroid dehydrogenase type 2 (11β-
HSD2) catalyzes the inactivation of cortisol to 
cortisone, while the opposing type 1 enzyme (11β-
HSD1) reverses the reaction, promoting cortisol 
production (Oakley and Cidlowski, 2013). Thus, the 
relative activities of these enzymes within a cell 
confer control over the local availability of cortisol. 
Of note, most synthetic glucocorticoids are not 
inactivated by 11β-HSD2 and their activities are 
preserved despite cellular upregulation of 11β-
HSD2 (Oakley and Cidlowski, 2013). 

As GRα is the biologically relevant isoform, all 
references henceforth to GR will imply GRα (Mata-
Greenwood et al., 2015). GR encompasses three 
functional domains including an amino-terminal 



 
 
 
 
 

 
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transactivation domain, a central DNA-binding 
domain, and a carboxy-terminal ligand-binding 
domain (Joseph and Whirledge, 2017). There is a 
flexible hinge region that contains a nuclear 
localization signal between the DNA-binding 
domain and the ligand-binding domain (Fig. 3). It 
is within this flexible hinge region that genomic 
interactions occur (Joseph and Whirledge, 2017). In 
the nucleus, GR homodimers bind to GR response 
elements (GRE) within promoter regions of target 
genes (Luisi et al., 1991). The consensus GRE 
sequences are comprised of two hexameric half-
sites separated by a spacer of three nucleotides 

(e.g., AGAACAnnnTGTTCT) (Strahle et al., 1987). 
Once GR homodimers bind to GREs, chromatin is 
remodeled, co-regulators are recruited, and GR-
induced transcription is initiated (Joseph and 
Whirledge, 2017). In addition to activation of GR-
target genes, GR may also negatively repress 
genes (Surjit et al., 2011). This occurs when GR 
binds to GREs with consensus sequence CTCC(n)0-

2GGAGA and co-repressors are recruited (Surjit et 
al., 2011). GR also mediates gene transcription via 
interactions with other transcription factors (Joseph 
and Whirledge, 2017). 

 

 

Fig. 3 NR3C1 (GR) domain structure. The domain structure of GRα is composed of an N-terminal 
modulatory domain, a DNA-binding domain, a hinge region, a ligand-binding domain, and a C-terminal 
ligand binding domain. Regions involved in transcriptional activation, dimerization, glucocorticoid binding, 
and DNA binding are indicated. The nuclear localization signal is located within the flexible hinge region. 
For comparison, the domain structures of GRβ and AR and its splice variant AR-v7 are included. Note the 
structural similarities between these transcription factors. AR, androgen receptor, ARE, androgen response 
element; CE3, cryptic exon 3; DBD, DNA-binding domain; DNA, deoxyribonucleic acid; GR, glucocorticoid 
receptor; GRE, glucocorticoid response element; LBD, ligand-binding domain; NTD, N-terminal domain. 



 
 
 
 
 

 
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GR signaling in AAs. GR signaling is triggered by a 
variety of physiological and environmental factors 
(Joseph and Whirledge, 2017). Chronic stress 
resulting in sustained elevated glucocorticoid 
exposure throughout a lifetime has negative 
physiological consequences (Cohen et al., 2006; 
Joseph and Whirledge, 2017; Williams et al., 2010; 
Zannas et al., 2015). Constant GRE binding induces 
local lasting changes in DNA methylation, shaping 
subsequent responses to stressors and 
glucocorticoids (Klengel et al., 2013; Thomassin et 
al., 2001; Wiench et al., 2011a; Wiench et al., 2011b; 
Zannas and West, 2014). It is therefore plausible 
that chronic stress confers cumulative effects on 
DNA methylation sites with long-term epigenetic 
ramifications (Zannas et al., 2015). Profound 
changes in DNA methylation are associated with 
aging-related diseases (Bjornsson et al., 2008; 
Christensen et al., 2009; Hernandez et al., 2011; 
Heyn et al., 2012; Horvath, 2013; Horvath et al., 
2012; Rakyan et al., 2010). Because of this, several 
DNA methylation-based predictors of aging have 
been recently developed (Bocklandt et al., 2011; 
Hannum et al., 2013; Horvath, 2013; Weidner et al., 
2014).  For example, a composite predictor 
comprised of 353 Cytosine-phosphate-Guanosine 
sites (CpGs) across the genome was shown to 
strongly correlate with chronological age across 
multiple human tissues (Horvath, 2013). Several 
studies have used this predictor to calculate 
accelerated epigenetic aging, defined as the 
difference between DNA-methylation-predicted 
age and chronological age (Boks et al., 2015; 
Horvath, 2015; Marioni et al., 2015a; Marioni et al., 
2015b). This accelerated epigenetic aging has been 
associated with cancer, obesity, PTSD, physical and 
cognitive decline, all-cause mortality, lower SES, 
and cumulative lifetime stress (Boks et al., 2015; 

Horvath, 2013; Marioni et al., 2015a; Zannas et al., 
2015). 

Cumulative lifetime stress has been associated with 
accelerated epigenetic aging in AAs (Zannas et al., 
2015). This is attributed to altered GR signaling 
marked by an increased number of epigenetic 
clock CpGs located within functional GREs, 
dynamic methylation changes following exposure 
to dexamethasone, and dynamic regulation by 
genes with enriched association for aging-related 
diseases which neighbored these CpGs (Zannas et 
al., 2015). These results support a model of stress-
induced accelerated epigenetic aging mediated by 
the lasting effects of chronic stressor exposure and 
aberrant glucocorticoid signaling on the 
epigenome (Zannas et al., 2015). 

AAs also appear to have amplified GR signaling 
and increased glucocorticoid resistance (Frazier et 
al., 2010). This was reported in a study that 
explored the role of body weight and body 
composition in insulin resistance among 
participants who were treated with placebo or 4 
mg dexamethasone (Frazier et al., 2010). Results 
revealed that AAs were significantly more 
hyperinsulinemic after dexamethasone treatment 
than EAs, indicated by higher peak insulin and 
postprandial insulin (Frazier et al., 2010). AAs were 
also found to be more insulin resistant as 
determined by fasting insulin and homeostatic 
model assessment (Frazier et al., 2010). This 
hyperinsulinemia and increased insulin resistance 
in AAs was independent of body weight or 
composition (body mass index, percent body fat, 
waist circumference), suggesting that amplified GR 
signaling was more prevalent in the AA study 
participants (Frazier et al., 2010). In another study, 
AAs showed increased activity in pro-inflammatory 
pathways and GR signaling, compared to EAs, 



 
 
 
 
 

 
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which was linked to exposure to discrimination 
(Thames et al., 2019). 

Taken together, the studies discussed above 
provide support for our model (Fig. 1) which links 
chronic exposure to stressors (low SES, 
discrimination, neighborhood effects, lesser 
education status) to elevated cortisol and amplified 
GR signaling. This amplified GR signaling could be 
exacerbated during the current COVID-19 
pandemic, given the chronic psychosocial stress 
disproportionately affecting minority populations, 
particularly AAs, during this pandemic (Holmes et 
al., 2020). The implications of this increased GR 
signaling for PCa progression and resistance to 
therapy is discussed below. 

GR signaling in PCa. GR has recently emerged as a 
major driver of PCa progression and resistance to 
AR-signaling inhibitor (ARSI) therapy, 
chemotherapy, and radiotherapy (Arora et al., 
2013; Beer et al., 2017; Chen et al., 2019; Claessens 
et al., 2017; Kroon et al., 2016; Li et al., 2017; 
Montgomery et al., 2014; Narayanan et al., 2016; 
Puhr et al., 2018; Sartor et al., 2014). A seminal 
study by Sawyers and colleagues identified GR 
overexpression as a common feature of ARSI-
resistant PCa tumors using pre-clinical models and 
confirmed in patient samples (Arora et al., 2013). 
GR overexpression in ARSI-resistant PCa cells and 
tissues have since been validated in cellular 
models of resistance and patient biospecimens 
(Isikbay et al., 2014; Li et al., 2017; Puhr et al., 2018). 
Growth factors produced in prostate stroma 
regulate glandular epithelial proliferation and 
differentiation, and steroid hormones including 
glucocorticoids are important modulators of 
stromal-epithelial cell signaling interactions in the 
prostate (Hidalgo et al., 2011; Taylor and 
Risbridger, 2008). GR-mediated transcriptional 

activity has been found to be altered in 
carcinoma-associated stroma and confers cell-
specific effects with the potential to induce anti-
androgen therapy resistance (Hidalgo et al., 2011; 
Zhao et al., 2014). 

 Significant structural similarities (Fig. 3) and 
transcriptomic overlap between AR and GR 
accounts for GR-mediated bypass of AR blockade 
(Sahu et al., 2013). In addition, there is overlap in 
the transcription protein interactome of both 
nuclear receptors (Lempiainen et al., 2017). 
Induction of GR expression is also accompanied in 
ARSI-resistant tissues by the loss of 11B-HSD2, 
resulting in increased stability of intratumoral 
cortisol (Li et al., 2017). The implications of these 
initial findings have sparked great interest, as PCa 
patients are routinely administered synthetic 
glucocorticoids (e.g. prednisone and 
dexamethasone) alongside ARSI and taxane 
chemotherapy for palliative purposes (Chi et al., 
2017; Collins et al., 2007; Narayanan et al., 2016; 
Tannock et al., 1989). Furthermore, the 
mechanisms underlying ARSI-resistance in PCa 
and their contribution to disease progression had 
not been fully previously elucidated, and these 
findings paved the way for research on the role of 
GR in these processes (Narayanan et al., 2016). 

While anti-androgen therapy is highly effective in 
producing an initial period of PCa regression, 
mCRPC eventually develops for many patients, 
characterized by rapidly rising PSA levels, even 
though circulating testosterone levels are in the 
typical castration range (<50 ng/dl) (Chen et al., 
2004; Feldman and Feldman, 2001; Lamont and 
Tindall, 2011; Schrecengost and Knudsen, 2013; 
Sharifi, 2013). This means that AR-target genes are 
operating in the absence of androgen to stimulate 
PCa cell survival, growth, and PSA secretion 



 
 
 
 
 

 
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(Narayanan et al., 2016). To understand the 
prospect of GR bypassing the AR signaling 
pathway and directly activating AR-target genes 
(Fig. 4), the similarities between AR and GR must 
be considered. AR and GR belong to the same 
intracellular receptor family of transcriptional 
regulators, and the DNA binding domains of AR 
and GR are highly conserved with an 80% match 
in amino acid sequence (Mangelsdorf et al., 1995; 
Narayanan et al., 2016; Rundlett and Miesfeld, 
1995). As shown in Fig. 3 the domain structures of 
GR and AR are very similar. Like GREs, AR 
response elements (AREs) in the promoter regions 
of AR-target genes are composed of a 15 base 
pair binding sequence comprised of two hexamer 
half-sites and separated by a 3 base pair spacer 
(Bolton et al., 2007). This similarity allows GR to 
interact with AREs and alter the expression of AR-
target genes in the absence of androgens (Arora 
et al., 2013). While that study identified 52 

common overlapping genes out of 105 AR 
signature genes and 121 GR signature genes, 
several canonical AR-target genes were found to 
be regulated by GR, including PCa key genes KLK3 
(encoding PSA) and TMPRSS2 (involved in fusions 
with ERG in a race-related manner)  (Arora et al., 
2013). Also, GR expression is normally repressed in 
PCa cells in the presence of AR, however this study 
demonstrated that AR blockade removes this GR 
inhibition and stimulates GR amplification (Arora et 
al., 2013). Intriguingly, the TMPRSS2 protein is a 
key receptor used by SARS-Cov-2 virus to infect 
host cells, which has prompted recent speculation 
that race-related and gender-related differences in 
AR signaling may explain in part the racial and 
gender variations in COVID-19 deaths and that 
anti-androgen agents combined with TMPRSS2 
inhibitors could potentially decrease disease 
severity (McCoy et al., 2020). 

 

 

Fig. 4 The interplay between GR and AR in the context of PCa. AR and GR belong to the same intracellular 
receptor family of transcriptional regulators and their DNA binding domains are highly conserved. GREs 



 
 
 
 
 

 
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and AREs in the promoter regions of GR-and AR-target genes are also similar and are composed of a 15 
base pair binding sequence with 2 hexamer half-sites separated by a 3 base pair spacer. GR expression is 
normally repressed in PCa cells in the presence of AR. However, an AR blockade removes GR inhibition 
and stimulates GR amplification allowing GR to interact with AREs and alter the expression of AR-target 
genes. This complex AR-GR interplay creates a major clinical dilemma as the effects of glucocorticoids can 
be beneficial and/or harmful to patients. 

Treatment options for prostate cancer patients 
The interplay between GR and AR in the context of 
PCa treatment presents a major clinical dilemma 
because the effects of glucocorticoids are both 
beneficial and harmful to patients (Arora et al., 
2013; Claessens et al., 2017; Montgomery et al., 
2014; Narayanan et al., 2016; Puhr et al., 2018; 
Sartor et al., 2014). AR signaling has been 
traditionally considered as the key actionable 
driver of PCa recurrence and progression 
(Banerjee et al., 2018). Because of this, targeting 
androgen biosynthesis and AR has been a 
standard of care for PCa treatment for over seven 
decades (Huggins and Hodges, 1972). Huggins 
and colleagues made the seminal observation that 
both surgical castration and estrogen 
administration resulted in regression of PCa 
metastasis (Huggins and Hodges, 1972), which led 
to the development of androgen deprivation 
therapy (ADT). Both agonists and antagonists of 
luteinizing hormone-releasing hormone (LHRH) 
are typically used as first-line ADT in patients with 
hormone-sensitive PCa to decrease endogenous 
testosterone production through the 
hypothalamic-pituitary-testicular (HPT) axis. There 
are also first-line anti-androgens that bind to AR 
and inhibit its activity including flutamide, 
bicalutamide, and nilutamide (Boccon-Gibod et al., 
1997; Kolvenbag and Nash, 1999; Todd et al., 
2005). 

While ADT with first-line anti-androgens is initially 
successful in most PCa patients who choose this 

option after biochemical recurrence, resistance to 
this therapy is inevitable, occurring within 18-24 
months (Asmane et al., 2011). Prostatic epithelial 
cells demonstrate great plasticity in response to 
ADT, giving rise to a highly heterogeneous co-
existence of AR-positive and AR-negative cells 
(Banerjee et al., 2018). A relatively short time after 
development of ADT-resistance, the patient enters 
a disease stage referred to as mCRPC, which 
typically has a 5-year survival rate of 30% (Scher et 
al., 2004; Thoreson et al., 2014). Therapeutic 
options for patients with mCRPC include ARSI, 
immunotherapy, radiation therapy with radium-
223, and taxane-based chemotherapy with 
docetaxel (DTX) or cabazitaxel (CBZ) plus the 
glucocorticoids dexamethasone or prednisone 
(Arlen and Gulley, 2005; Corn et al., 2017; Gilbert 
and Parker, 2005). Second-line, next-generation 
ARSIs such as enzalutamide and apalutamide have 
been developed during the past decade for PCa 
patients who have failed LHRH 
agonists/antagonists or other first-line anti-
androgens (Banerjee et al., 2018). Another clinically 
relevant ARSI, abiraterone, is an inhibitor of 
androgen biosynthesis that acts by blocking the 
activity of cytochrome P450 17 alpha-hydroxylase 
(CYP17), a key enzyme that is essential for the 
generation of the androgen precursor 
dehydroepiandrosterone (DHEA) (Rehman and 
Rosenberg, 2012). 

DTX and/or CBZ can extend patient survival by a 
few months, but chemoresistance develops, 



 
 
 
 
 

 
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curtailing the beneficial effects of these taxane 
drugs (Arlen and Gulley, 2005; Corn et al., 2017; 
Gilbert and Parker, 2005). Although not all PCa 
patients that fail anti-androgen therapy undergo 
chemotherapy, results from the recent clinical trials 
CHAARTED and STAMPEDE showed that 
administering DTX together with anti-androgen 
therapy in newly diagnosed mCRPC patients 
provides a dramatic increase in overall survival 
advantage compared to ADT alone (James et al., 
2016; Kyriakopoulos et al., 2018). Other recent trials 
combining emerging therapies or modifying the 
sequence of available therapies have yielded 
promising results for the treatment of mCRPC (Ku 
et al., 2019; Schmid and Omlin, 2020). 

Because of the tumor heterogeneity observed 
within and among PCa patients, developing 
effective therapies for this malignancy remains 
challenging (Ku et al., 2019; Maitland et al., 2019). 
Despite the spectrum of therapeutic options for 
mCRPC which provide increased overall survival 
benefits with improved quality of life, this 
advanced stage of the disease still remains 
incurable due to the development of therapy 
resistance. A promising emerging therapy for 
mCRPC based on prostate specific membrane 
antigen (PSMA) theranostics, which combines 
positron emission tomography (PET) imaging with 
tumor targeting, is bringing hope to the diagnosis 
and treatment of men with advanced PCa 
(Kratochwil et al., 2019). PSMA is a transmembrane 
glycoprotein that is highly expressed in PCa, 
particularly in high grade tumors or mCRPC, with 
minimal or no expression in normal tissues (Silver 
et al., 1997). Currently, a PSMA specific ligand 
labeled with a positron emitter is a desirable 
diagnostic tool for detecting metastatic disease at 
much lower PSA levels than conventional imaging. 
Patients with high PSMA tumor expression can 

then undergo targeted radioligand therapy using 
the same PSMA ligand labeled with a beta emitter 
(e.g. 177lutetium) or an alpha emitter (e.g. 
225actinium) to selectively destroy the cancer cells 
without damaging normal tissues (Baum and 
Kulkarni, 2012). The implementation of PSMA 
theranostics in clinical practice has the potential to 
revolutionize mCRPC treatment and improve 
patient outcomes. Prospective randomized clinical 
trials are currently underway worldwide to validate 
PSMA theranostics compared to available standard 
of care therapies for mCRPC. The optimal timing 
for administering this therapy relative to the 
sequence of other therapies has yet to be defined. 

Glucocorticoids in PCa treatment 
The synthetic glucocorticoids prednisone and 
dexamethasone are routinely used therapeutically 
and have much higher potency than cortisol in 
activating GR. For example, 4 mg of prednisone 
and 0.75 mg of dexamethasone provide the 
physiological equivalent of 20 mg of 
cortisol.(Narayanan et al., 2016) Prednisone is 
clinically used in doses of 5-10 mg once or twice 
per day and dexamethasone is used in doses at 
0.75-1 mg once or twice per day (Narayanan et al., 
2016). When co-administered with taxane 
chemotherapy for PCa, their potent anti-
inflammatory properties counteract pain, nausea, 
lack of appetite, fatigue, hypersensitivity, and fluid 
retention (de Bono et al., 2010; Dorff and 
Crawford, 2013; Lafeuille et al., 2013; Schwartz, 
2012; Tannock et al., 2004). 

While the benefits of glucocorticoid co-
administration to PCa patients have been 
established, there is evidence that increased GR 
signaling could also be detrimental to these 
patients (Arora et al., 2013; Claessens et al., 2017; 
Isikbay et al., 2014; Kroon et al., 2016; Li et al., 2017; 



 
 
 
 
 

 
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Montgomery et al., 2014; Narayanan et al., 2016; 
Puhr et al., 2018; Sartor et al., 2014). One study by 
Puhr et al. found that GR expression is initially 
reduced in primary PCa tissue, but is restored in 
metastatic lesions (Puhr et al., 2018). This group 
also found that genetic or pharmacological 
inhibition of GR impaired the proliferation and 3D 
spheroid-forming capabilities of PCa cell lines 
(Puhr et al., 2018). Additionally, these investigators 
also reported that GR levels increase in DTX-
resistant PCa cell lines and in tissues from patients 
who have been treated with DTX, and that patients 
who relapse with biochemical recurrence and have 
high GR levels experience shortened progression-
free survival (Puhr et al., 2018). There are also 
reports that PCa patients enrolled in clinical trials 
have worse overall survival outcomes when 
receiving glucocorticoids compared to patients not 
receiving glucocorticoids (Montgomery et al., 2014; 
Montgomery et al., 2015; Narayanan et al., 2016). 
This trend was observed in the AFFIRM phase 3 
clinical trial evaluating the use of enzalutamide as 
well as in the COU-AA-301 phase 3 clinical trial in 
which patients were randomized to prednisone 
plus abiraterone after failing taxane chemotherapy 
(de Bono et al., 2011; Narayanan et al., 2016). On 
the other hand, recent results from the SWITCH 
trial showed that in selected clinically stable 
mCRPC patients with limited disease progression, 
the combination of abiraterone with 
dexamethasone provided a benefit, measurable by 
PSA decline and disease stabilization, to patients 
with normal AR status but not patients with AR 
aberrations (Romero-Laorden et al., 2018). One 
limitation of this study, however, was the lack of a 
molecular analysis that included predictive 
biomarkers such as the AR-v7 splicing variant (Fig. 
3), also implicated in both ARSI and taxane 

resistance, and GR expression or signaling 
(Romero-Laorden et al., 2018). 

Our group recently demonstrated the ability of 
liganded GR to upregulate the expression of 
clusterin (CLU) and lens epithelium-derived growth 
factor of 75 kD (LEDGF/p75), two stress 
oncoproteins previously established as key 
contributors to therapy resistance in various 
cancer types, in racially diverse preclinical PCa 
cellular models (Chun, 2014; Djeu and Wei, 2009; 
Huang et al., 2007; July et al., 2002; Koltai, 2014; 
Matsumoto et al., 2013; Mediavilla-Varela et al., 
2009; Rios-Colon et al., 2017; Woods-Burnham et 
al., 2018a). This upregulation could be reversed by 
blocking GR signaling with the steroidal antagonist 
mifepristone (RU-486) or GR knockdown (Woods-
Burnham et al., 2018a). The particular observation 
of high endogenous CLU expression in the AA PCa 
cell line MDA-PCa-2b suggests that downstream 
effects of GR signaling such as the upregulation of 
genes associated with therapy-resistance may be 
exaggerated in AA PCa patients, and is consistent 
with the emerging notion that GR signaling is 
enhanced in the AA population (Frazier et al., 
2010; Woods-Burnham et al., 2018a; Zannas et al., 
2015). Our recent study also revealed higher 
median values of GR in AA prostate tissues 
compared to EA prostate tissues using the Taylor 
and Wallace datasets within the Oncomine 
database, supporting the premise that AA men 
with PCa may have enhanced intratumoral GR 
signaling (Woods-Burnham et al., 2018a). 

Regardless of whether GR drives resistance to ARSI 
by activating AR-target genes only or also by 
activating an independent transcriptome that 
drives therapy resistance, it is becoming very clear 
that GR plays a major role in the progression of 
mCRPC. There remains an urgent need, however, 



 
 
 
 
 

 
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to further elucidate genes driven by GR signaling 
that are specifically associated with ARSI-resistance 
while also identifying precise genes that have been 
linked to taxane chemotherapy. This is critical to 
our understanding of mechanisms by which GR 
may contribute to therapy resistance, supporting 
the development of novel therapeutic strategies. 
Furthermore, given that AA men suffer from 
disproportionate PCa incidence and mortality as 
well as an enhanced physiological response to 
glucocorticoids, additional studies are warranted 
to fully elucidate the interplay between GR 
signaling and PCa tumor aggressiveness 
specifically in this racial/ethnic group. 

Given the emerging role of GR signaling in PCa 
progression, we propose that cumulative 
psychosocial stress leading to chronically elevated 
cortisol levels, increased GR expression, and 
sustained GR signaling in AA men over time could 
predispose them to develop aggressive PCa 
tumors as well as prime them towards poor 
response to conventional treatments (Fig. 1). 

Therapeutic GR Modulators. The emerging 
contribution of GR signaling to PCa therapy 
resistance has led to increasing efforts to 
therapeutically target this signaling as a potential 
treatment for mCRPC. A phase I/II clinical trial 
(NCT02012296) is currently ongoing to determine 
if combination therapy with enzalutamide and 
mifepristone, a GR antagonist that delayed mCRPC 
in pre-clinical models, extends the time to PSA 
progression. Because complete antagonism of GR 
may introduce adverse systemic consequences, 
highly selective GR modulators (SGRMs) that target 
this receptor in specific tissues are currently under 
development and are being evaluated in pre-
clinical models of mCRPC (Hunt et al., 2018; Kach 
et al., 2017; Nguyen et al., 2017). The specificity of 

these new generation modulators are often 
dependent upon their superior selectivity for GR 
over other steroid receptors, which is a 
characteristic of mifepristone (Baulieu, 1991; Hunt 
et al., 2018; Kach et al., 2017; Meijer et al., 2018; 
Nguyen et al., 2017). For example, the SGRM 
CORT118335 has a high GR affinity with only 
modest MR affinity (Atucha et al., 2015; Hunt et al., 
2012; Nguyen et al., 2017). This and another SGRM, 
CORT108297, showed ability to block GR 
transcriptional activity and slow CRPC progression 
in pre-clinical models, and unlike mifepristone did 
not affect AR signaling (Kach et al., 2017). Another 
SGRM, CORT125134, was shown to reverse the 
effects of prednisone without binding to 
progesterone receptor (PR) and is well tolerated in 
humans. However, it should be noted that the 
overwhelming majority of study participants were 
EA males and the study did not take into account 
potential racial or ethnic differences in GR 
signaling (Hunt et al., 2018). An additional 
determinant of the ability of GR modulators to 
bind to specific tissues is the presence or lack of 
GR co-regulators that may either serve as 
coactivators or corepressors (Hunt et al., 2018; 
Lonard and O'Malley, 2012; Meijer et al., 2018; 
Nguyen et al., 2017). GREs in different genes 
depend on particular sets of coactivators (Lachize 
et al., 2009; Meijer et al., 2018; Zalachoras et al., 
2016). Selective GR modulators that act via GREs 
may differ in their ability to induce interactions 
with other transcription factors that bind DNA in 
the vicinity of the GREs (Meijer et al., 2018). 

The ability to treat a specific disease independently 
from all the other GR-dependent effects would be 
considered a “game changer” in medicine (De 
Bosscher et al., 2016; Meijer et al., 2018). To that 
end, SGRMs are being introduced in clinical trials 
for PCa patients. A current trial seeks to establish 



 
 
 
 
 

 
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the recommended dose, safety, pharmacokinetics, 
pharmacodynamics, and preliminary antitumor 
activity of the specific GR antagonist ORIC-101 in 
combination with enzalutamide in mCRPC patients 
(NCT04033328) (Multani, 2019). A similar trial is 
underway to examine the same primary outcomes 
using a different GR antagonist, CORT125281 
(NCT03437941) (Shepherd, 2018). Given the 
potential role of GR in promoting DTX resistance, 
future pre-clinical studies and clinical trials 
evaluating selective GR modulation in combination 
with taxane drugs for patients with mCRPC are 
warranted. 

Conclusions and future perspectives 
Emerging data support the notion that PCa health 
disparities are influenced by the interplay between 
socioeconomic, psychosocial, health care, and 
biological/genetic factors. Chronic and amplified 
GR signaling triggered by cumulative psychosocial 
stress may negatively influence health outcomes in 
AA men by promoting the activation of molecular 
pathways that contribute to PCa progression (Fig. 
1). This enhanced GR signaling, combined with 
diminished access to health care and genetic 
drivers of PCa that increase risk of aggressive 
disease in AA men may promote a more 
aggressive tumor phenotype, including the 
possibility of increased resistance to standard 
therapies (Fig. 1). However, it remains to be 
determined if mCRPC therapies involving 
glucocorticoids such as dexamethasone or 
prednisone produce lower benefits in AA patients 
compared to EA patients. Likewise, it remains to 
be determined if AA men with mCRPC may benefit 
more from combinatorial therapies involving GR 
antagonists such as mifepristone and SGRMs 
compared to EA patients. Critical for addressing 
these issues is the recruitment and retention of 
large numbers of AA PCa patients to current and 

future clinical trials examining the contribution of 
glucocorticoids or GR antagonists to overall 
patient survival. It would therefore be of great 
interest to determine if there are racial differences 
in the outcomes of the SWITCH trial (abiraterone 
plus dexamethasone), the NCT02012296 trial 
(enzalutamide plus mifepristone), the 
NCT03437941 trial (enzalutamide plus the GR 
antagonist CORT125281), and the NCT0403328 
trial (enzalutamide plus the GR antagonist ORIC-
101). 

As our understanding of the contribution of GR 
signaling to PCa progression and therapy 
resistance increases, clinicians and researchers 
must consider carefully the clinical implications of 
standard and upcoming treatments for PCa that 
modulate GR function in AA men. It is probable 
that ongoing clinical trials may reveal race-related 
differential benefits, or harms, of modulating GR 
function for mCRPC treatment. This would 
necessitate clinical and socio-behavioral scientists 
working together to measure psychosocial 
indicators linked to increased GR signaling in AA 
PCa patients. Socio-behavioral scientists and 
clinicians could also implement novel community- 
and clinic-based interventions to reduce chronic 
stress, which may result in attenuated GR signaling 
and, potentially, better outcomes for AA men, who 
are most at risk of developing aggressive PCa. 
Finally, preventive policy interventions targeting 
upstream determinants of SES including education, 
housing, urban planning, community 
development, employment, and income 
enhancements should be considered to ameliorate 
the discriminatory contributors to chronic 
psychosocial stress experienced by African 
American men. 

Funding Sources 



 
 
 
 
 

 
www.companyofscientists.com/index.php/chd                   e20                                              Cancer Health Disparities 

RESEARCH 

The authors acknowledge research support from 
the National Institutes of Health (NIH) grants 
R21CA226654-01A1 (C.A.C) and P20MD006988-
Project 2 (C.A.C.), the Loma Linda University 
Health (LLUH) Center for Health Disparities and 
Molecular Medicine (C.A.C. and S.M) and the LLUH 
Schools of Medicine (C.A.C, H.C.R., F.G.A), 
Behavioral Health (S.M.), and Nursing (L.R.R). 
L.W.B., S.R.M., and E.S.S.H. were supported by NIH 
grant R25GM060507 and the LLU-NIH Initiative for 
Maximizing Student Development (IMSD) graduate 
training program. E.S.S.H. is currently supported 
by NIH grant R21CA226654-01A1S1. L.W.B. is 
currently supported by NIH grant T32 CA186895. 

Acknowledgements 
The authors thank Dr. Marino De Leon, Director of 
the LLUH Center for Health Disparities and 
Molecular Medicine, for his support of this work. 
We also thank the members of this center and 
many other colleagues for stimulating discussions 
leading to the writing of this comprehensive 
review paper.  

Conflict of interest 
The authors declare that no competing or conflict of 
interests exist. The funders had no role in study 
design, writing of the manuscript, or decision to 
publish. 

Authors’ contributions 
L.W.B., L.S., S.M., and C.A.C. contributed to the 
conceptual design of the original research topic. 
L.W.B. wrote the initial version of the manuscript 
and prepared Fig. 1. S.R.M. wrote the sections on 
GR biology.  H.R.C. contributed to the section on 
prostate cancer treatment options. F.G.A. wrote 
the section on PSMA theranostics. E.S.S.H. 
prepared Figs. 2, 3, and 4, and cross-checked for 
accuracy the literature citations throughout the 

manuscript. M.C.S., L.R.R., and D.R.W. provided 
unique perspectives that guided the writing of 
sections related to socioeconomic and 
psychosocial aspects of PCa.  L.W.B., L.S., and 
C.A.C. edited the various drafts of the manuscript. 
All authors reviewed and approved the manuscript 
prior to submission. 

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