Clinical and genomic crosstalk between glucocorticoid receptor and estrogen receptor α in endometrial cancer

Abstract

Steroid hormone receptors are simultaneously active in many tissues and are capable of altering each other's molecular and biological roles. Estrogen receptor ɑ (ER) and glucocorticoid receptor (GR) are co-expressed in the uterus and their ligands have opposing effects on uterine growth and morphology, with estrogens inducing growth and corticosteroids inhibiting growth. In endometrioid-type endometrial tumors expressing ER, we surprisingly found that the expression of GR is associated with poor prognosis and higher tumor grade. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished once estrogen-induced endometrial hyperplasia was established and cancer cells increased growth when treated with dexamethasone and estradiol. To understand the underlying molecular crosstalk between ER and GR in endometrial cancer cells, we measured their genomic binding following treatment with estradiol, dexamethasone, and the combination. We found 20% overlap in bound loci when ER and GR are induced with their respective ligands individually; however, upon induction with both ligands simultaneously they co-occupy significantly more sites (47%). ER binding is only slightly affected by the presence of dexamethasone, while GR binding is significantly altered by the presence of estradiol with GR being recruited to loci bound by ER that contain estrogen response elements. The GR sites gained in the presence of estradiol consist of loci that become more accessible upon estradiol induction, supporting a model where ER assists in the chromatin loading of GR. The crosstalk in genomic binding is associated with gene expression changes upon cotreatment being more similar to estradiol than dexamethasone, but with novel regulated genes including a decrease in cell-cell adherens junction genes. Our results suggest both a phenotypic and molecular interplay between ER and GR in endometrial cancer.