The Co-Expression of Estrogen Receptors ERα, ERβ, and GPER in Endometrial Cancer

Estrogens have important roles in endometrial cancer (EC) and exert biological effects through the classical estrogen receptors (ERs) ER alpha and ER beta, and the G-protein-coupled ER, GPER. So far, the co-expression of these three types of ERs has not been studied in EC. We investigated ER alpha, ER beta, GPER mRNA and protein levels, and their intracellular protein distributions in EC tissue and in adjacent control endometrial tissue. Compared to control endometrial tissue, immunoreactivity for ER alpha in EC tissue was weaker for nuclei with minor, but unchanged, cytoplasmic staining; mRNA and protein levels showed decreased patterns for ER alpha in EC tissue. For ER beta, across both tissue types, the immunoreactivity was unchanged for nuclei and cytoplasm, although EC tissues again showed lower mRNA and protein levels compared to adjacent control endometrial tissue. The immunoreactivity of GPER as well as mRNA levels of GPER were unchanged across cancer and control endometrial tissues, while protein levels were lower in EC tissue. Statistically significant correlations of estrogen receptor alpha (ESR1) versus estrogen receptor beta (ESR2) and GPER variant 3,4 versus ESR1 and ESR2 was seen at the mRNA level. At the protein level studied with Western blotting, there was significant correlation of ER alpha versus GPER, and ER beta versus GPER. While in clinical practice the expression of ER alpha is routinely tested in EC tissue, ER beta and GPER need to be further studied to examine their potential as prognostic markers, provided that specific and validated antibodies are available.