The Role of Glucocorticoids in Breast Cancer Therapy

Abstract

Glucocorticoids (GCs) are anti-inflammatory and immunosuppressive steroid molecules secreted by the adrenal gland and regulated by the hypothalamic–pituitary–adrenal (HPA) axis. GCs present a circadian release pattern under normal conditions; they increase their release under stress conditions. Their mechanism of action can be via the receptor-independent or receptor-dependent pathway. The receptor-dependent pathway translocates to the nucleus, where the ligand-receptor complex binds to specific sequences in the DNA to modulate the transcription of specific genes. The glucocorticoid receptor (GR) and its endogenous ligand cortisol (CORT) in humans, and corticosterone in rodents or its exogenous ligand, dexamethasone (DEX), have been extensively studied in breast cancer. Its clinical utility in oncology has mainly focused on using DEX as an antiemetic to prevent chemotherapy-induced nausea and vomiting. In this review, we compile the results reported in the literature in recent years, highlighting current trends and unresolved controversies in this field. Specifically, in breast cancer, GR is considered a marker of poor prognosis, and a therapeutic target for the triple-negative breast cancer (TNBC) subtype, and efforts are being made to develop better GR antagonists with fewer side effects. It is necessary to know the type of breast cancer to differentiate the treatment for estrogen receptor (ER)-positive, ER-negative, and TNBC, to implement therapies that include the use of GCs.

Investigating the crosstalk between chronic stress and immune cells: implications for enhanced cancer therapy

“…Furthermore, chronic stress weakens the apoptotic response of tumor cells triggered by chemotherapy, ultimately impairing the efficacy of cytotoxic agents. This impairment is exacerbated by stress-induced glucocorticoids, which increase cancer cell resistance and reduce the efficacy of multiple chemotherapy drugs, such as paclitaxel, doxorubicin, TRAIL, and fluorouracil ( Kanai et al, 2020 ; Cui et al, 2021 ; Butz and Patócs, 2022 ; Mitre-Aguilar et al, 2022 ). Additionally, NE inhibits c-Jun phosphorylation, mediated by JNK, through activation of the β 2-AR pathway, thereby attenuating the apoptosis of ovarian cancer cells induced by paclitaxel ( Kang et al, 2016 ; Chen et al, 2021 ).…”

Differential role of glucocorticoid receptor based on its cell type specific expression on tumor cells and infiltrating lymphocytes

“…In the context of BC, synthetic GCs are frequently employed as pre-medication alongside chemotherapy interventions 17 .…”

Differential role of glucocorticoid receptor based on its cell type specific expression on tumor cells and infiltrating lymphocytes

“…While GCs enhance innate immune responses, they concurrently suppress the adaptive immune pathway, potentially fostering a tumorigenic immune microenvironment [ 15 , 16 ]. In the context of BC, synthetic GCs are frequently employed as pre-medication alongside chemotherapy interventions [ 17 ].…”