Context-Dependent Role of Glucocorticoid Receptor Alpha and Beta in Breast Cancer Cell Behaviour

Abstract

Background. The dual role of GCs has been observed in breast cancer; however, due to many concomitant factors, GR action in cancer biology is still ambiguous. In this study, we aimed to unravel the context-dependent action of GR in breast cancer. Methods. GR expression was characterized in multiple cohorts: (1) 24,256 breast cancer specimens on the RNA level, 220 samples on the protein level and correlated with clinicopathological data; (2) oestrogen receptor (ER)-positive and -negative cell lines were used to test for the presence of ER and ligand, and the effect of the GRβ isoform following GRα and GRβ overexpression on GR action, by in vitro functional assays. Results. We found that GR expression was higher in ER− breast cancer cells compared to ER+ ones, and GR-transactivated genes were implicated mainly in cell migration. Immunohistochemistry showed mostly cytoplasmic but heterogenous staining irrespective of ER status. GRα increased cell proliferation, viability, and the migration of ER− cells. GRβ had a similar effect on breast cancer cell viability, proliferation, and migration. However, the GRβ isoform had the opposite effect depending on the presence of ER: an increased dead cell ratio was found in ER+ breast cancer cells compared to ER− ones. Interestingly, GRα and GRβ action did not depend on the presence of the ligand, suggesting the role of the “intrinsic”, ligand-independent action of GR in breast cancer. Conclusions. Staining differences using different GR antibodies may be the reason behind controversial findings in the literature regarding the expression of GR protein and clinicopathological data. Therefore, caution in the interpretation of immunohistochemistry should be applied. By dissecting the effects of GRα and GRβ, we found that the presence of the GR in the context of ER had a different effect on cancer cell behaviour, but independently of ligand availability. Additionally, GR-transactivated genes are mostly involved in cell migration, which raises GR’s importance in disease progression.

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

“…Genome wide target identification was evaluated by Pan et al to identify the regulated genes after GR activation [ 40 ]. Butz et al examined the positively and negatively correlating genes with GR expression [ 18 , 41 ]. GRsig derived in our study is unique in that it uncovers the pattern driven by GR both in ER+ and ER- BC.…”

“…The complexity in GR detection is attributed to the existence of at least two isoforms of the protein (GRα and GRβ) and various spliced variants of the mRNA. This molecular diversity contributes to the ambiguity in GR detection [ 18 ].…”