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.
