Functions of Glucocorticoids in Breast and Other Solid Cancers

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. Cells within the tumor micoenvironment may also contribute to the availability of cortisol to solid tumors. 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 disrupted, with great hour-to-hour variation and elevated concentrations at the afternoon nadir. Major depression and other chronic illnesses have been associated with increased serum cortisol levels, but breast cancer is unusual in that the opposing steroid DHEA is also elevated. Cortisol increases 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 promotes growth of solid tumors, mainly by providing a substrate for growth and by suppression of host defenses. Glucocorticoid agonists may benefit therapies utilizing DNA damage response, retinoid therapy, and PARP1 therapy but may oppose therapies of ER- cancers and immune checkpoint blockade therapy. Cortisol is known to affect several physiological processes. Immunosuppressive activity has been well documented, but how all of the many activities interact to affect the growth of breast cancer has not been reviewed in recent years.