Glucocorticoids in breast cancer: physiologic mechanisms and relationship to risk, survival, and treatment response.
- 1Department of Obstetrics and Gynecology, Physiology and Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
- 2Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
Abstract
Almost every cell of the body expresses glucocorticoid receptors (GR). Cell density, isoform distribution, and responsiveness vary greatly among tissues with highest density in cells of the immune system. Well-documented basic studies describe functions of GR-cortisol complex in immune cells; inhibition of inflammation, promotion of apoptosis, inhibition of proliferation, and inhibition of transport into tissues. Basic studies also describe metabolic actions; promotion of gluconeogenesis, amino acid mobilization, impairment of insulin secretion, inhibition of glucose uptake, and expansion of visceral fat depots. Cortisol secretion is stimulated by psychological stress, and by physiological responses to pain, infection, and hypoglycemia. Stimulatory inputs from the brain on CRH and AVP biosynthesis, deficiencies in the negative feedback of cortisol, and insufficient stimulation of β-arrestin-1 by cortisol may all act to increase secretion of ACTH. Peripherally, cortisol activity is preserved by 11βHSD type I and is decreased at specific sites by 11βHSD type 2. In metastatic breast cancer, the normal circadian rhythm of serum and salivary cortisol is often disrupted, with great hour-to-hour variation and elevated concentrations during the afternoon nadir. Cortisol may increase cancer risk by making glucose available through glycogenolysis and gluconeogenesis, by inhibiting insulin promotion of glucose uptake, and by inhibiting IGF-I promotion of leukocytopoiesis, increasing the synthesis of glutamine synthetase, inhibiting ICAM-I and VCAM-1 for leukocyte recruitment, and increasing the expression of immune checkpoint receptors PD-1 and Tim3, and increasing Treg cells. Cortisol promotes the polarization of macrophages toward the anti-inflammatory M2 phenotype and decreases the M1 phenotype. It also binds to membrane-bound corticosteroid-binding globulin, activating adenylyl cyclase, suppressing T cell proliferation. Overall, elevated cortisol secretion may promote growth of breast cancer by providing a substrate for growth and by suppression of host defenses. However, by antagonizing the estrogen response the liganded receptor may inhibit the growth of estrogen-dependent breast cancer. This review is relevant at this time because of the many interactions of glucocorticoids with potential treatments for the several subtypes of breast cancer. Glucocorticoid agonists may benefit therapies utilizing DNA damage response, retinoid therapy, and PARP1 therapy but may oppose therapies of ER-negative cancers and immune checkpoint blockade therapy.
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BibTeX
@article{chatterton2026glucocorticoids,
title = {{Glucocorticoids in breast cancer: physiologic mechanisms and relationship to risk, survival, and treatment response.}},
author = {Robert T Chatterton and Peter H Gann},
journal = {Frontiers in endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1952560},
url = {https://europepmc.org/article/MED/42899147},
note = {CC BY},
}
RIS
TY - JOUR
TI - Glucocorticoids in breast cancer: physiologic mechanisms and relationship to risk, survival, and treatment response.
AU - Robert T Chatterton
AU - Peter H Gann
PY - 2026
DA - 2026/10/05
JO - Frontiers in endocrinology
DO - 10.3389/fendo.2026.1952560
UR - https://europepmc.org/article/MED/42899147
AB - Almost every cell of the body expresses glucocorticoid receptors (GR). Cell density, isoform distribution, and responsiveness vary greatly among tissues with highest density in cells of the immune system. Well-documented basic studies describe functions of GR-cortisol complex in immune cells; inhibition of inflammation, promotion of apoptosis, inhibition of proliferation, and inhibition of transport into tissues. Basic studies also describe metabolic actions; promotion of gluconeogenesis, amino acid mobilization, impairment of insulin secretion, inhibition of glucose uptake, and expansion of visceral fat depots. Cortisol secretion is stimulated by psychological stress, and by physiological responses to pain, infection, and hypoglycemia. Stimulatory inputs from the brain on CRH and AVP biosynthesis, deficiencies in the negative feedback of cortisol, and insufficient stimulation of β-arrestin-1 by cortisol may all act to increase secretion of ACTH. Peripherally, cortisol activity is preserved by 11βHSD type I and is decreased at specific sites by 11βHSD type 2. In metastatic breast cancer, the normal circadian rhythm of serum and salivary cortisol is often disrupted, with great hour-to-hour variation and elevated concentrations during the afternoon nadir. Cortisol may increase cancer risk by making glucose available through glycogenolysis and gluconeogenesis, by inhibiting insulin promotion of glucose uptake, and by inhibiting IGF-I promotion of leukocytopoiesis, increasing the synthesis of glutamine synthetase, inhibiting ICAM-I and VCAM-1 for leukocyte recruitment, and increasing the expression of immune checkpoint receptors PD-1 and Tim3, and increasing Treg cells. Cortisol promotes the polarization of macrophages toward the anti-inflammatory M2 phenotype and decreases the M1 phenotype. It also binds to membrane-bound corticosteroid-binding globulin, activating adenylyl cyclase, suppressing T cell proliferation. Overall, elevated cortisol secretion may promote growth of breast cancer by providing a substrate for growth and by suppression of host defenses. However, by antagonizing the estrogen response the liganded receptor may inhibit the growth of estrogen-dependent breast cancer. This review is relevant at this time because of the many interactions of glucocorticoids with potential treatments for the several subtypes of breast cancer. Glucocorticoid agonists may benefit therapies utilizing DNA damage response, retinoid therapy, and PARP1 therapy but may oppose therapies of ER-negative cancers and immune checkpoint blockade therapy.
SN - 1664-2392
ER -