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

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 GR beta isoform following GR alpha and GR beta 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. GR alpha increased cell proliferation, viability, and the migration of ER- cells. GR beta had a similar effect on breast cancer cell viability, proliferation, and migration. However, the GR beta 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, GR alpha and GR beta 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 GR alpha and GR beta, 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.

Automated summary

This study aimed to uncover the context-dependent action of glucocorticoid receptors (GR) in breast cancer. Through multiple cohorts, it was found that GR expression is higher in ER- breast cancer cells and GR-regulated genes are mainly involved in cell migration. The study also revealed that GR action is independent of ligand availability, highlighting its ligand-independent role in breast cancer. Therefore, caution should be applied in the interpretation of immunohistochemistry results, and the importance of GR in disease progression, particularly in cell migration, is emphasized.