A Brief Overview of the Paradoxical Role of Glucocorticoids in Breast Cancer

Abstract

Glucocorticoids (GCs) are stress hormones that play multiple roles in the regulation of cancer cell differentiation, apoptosis, and proliferation. Some types of cancers, such as hematological malignancies, can be effectively treated by GCs, whereas the responses of epithelial cancers to GC treatment vary, even within cancer subtypes. In particular, GCs are frequently used as supporting treatment of breast cancer (BC) to protect against chemotherapy side effects. In the therapy of nonaggressive luminal subtypes of BC, GCs can have auxiliary antitumor effects due to their cytotoxic actions on cancer cells. However, GCs can promote BC progression, colonization of distant metastatic sites, and metastasis. The effects of GCs on cell proliferation vary with BC subtype and its molecular profile and are realized via the activation of glucocorticoid receptor (GR), a well-known transcriptional factor involved in the regulation of the expression of multiple genes, cell-cell adhesion, and cell migration and polarity. This review focuses on the roles of GC signaling in the adhesion, migration, and metastasis of BC cells. We discuss the molecular mechanisms of GC actions that lead to BC metastasis and propose alternative pharmacological uses of GCs for BC treatment.

Impact of Glucocorticoid Use in Oncology in the Immunotherapy Era

“…Indeed, GC treatment was found to down-regulate basal and chemotherapy-induced expression of apoptosis effectors in human cervical and lung carcinoma cells [ 25 ]. Variations in effects have also been observed within tumours, and in breast cancer, variable effects were shown according to the histological subtype or according to the tumour microenvironment [ 21 , 26 , 27 , 28 ].…”

Mechanisms behind context-dependent role of glucocorticoids in breast cancer progression

“…GCs, especially dexamethasone (dex), are routinely administered as adjuvant therapy to manage the side effects of cytotoxic chemotherapy due to their antiemetic effects, energy and orexigenic properties, and to prevent hypersensitivity reactions. However, recently, it has been revealed that dex triggers different effects depending on the breast cancer molecular subtype, which has raised new concerns regarding the generalized use of GC, and suggests that the context-dependent effects of GCs and GC resistance can be taken into potential consideration during treatment design [ 6 - 8 ].…”

“…Transcriptome analysis and in vitro experiments suggest cellular processes, such as EMT, chromatin remodeling, and epithelial cell/inflammatory cell interactions in the involvement of GR in the aggressive behavior of ER-negative breast cancer [ 7 , 67 , 118 ]. Without ER coactivation, GR triggers several oncogenic signaling pathways, such as Wnt and Hippo, KLF5 (Kruppel-like factor 5) prosurvival transcription factor, and SGK1 (MKP-1 (MAPK phosphatase-1)) [ 6 , 8 ]. Even at distant metastatic sites, GR activation due to GC treatment promoted tumor cell colonization and reduced the overall survival by upregulating the expression of ROR-1 kinase (the receptor tyrosine kinase-like orphan receptor-1) [ 7 ].…”

Nutritional Sensor REDD1 in Cancer and Inflammation: Friend or Foe?

“…In accordance, REDD1-deficient immortalized murine embryonic fibroblasts demonstrated an increase in proliferative activity in xenografts [ 47 ], and the absence of REDD1 expression was characteristics for patients with carcinomas of unknown primary origin [ 48 ]. Several studies have shown that up-regulation of REDD1 after the application of various chemotherapeutics was associated with a decreased survival of breast cancer cells [ 49 , 50 , 51 ]. Furthermore, in HER2-positive and in triple-negative breast cancer, tumor cell proliferation and survival in the hypoxic tumor environment were associated with REDD1 down-regulation and HIF-1α stabilization [ 52 ].…”