Clinical and Genomic Crosstalk between Glucocorticoid Receptor and Estrogen Receptor α In Endometrial Cancer

• Published in: Cell reports (Cambridge) 2018-03, Vol.22 (11), p.2995-3005
• Main Authors: Vahrenkamp, Jeffery M., Yang, Chieh-Hsiang, Rodriguez, Adriana C., Almomen, Aliyah, Berrett, Kristofer C., Trujillo, Alexis N., Guillen, Katrin P., Welm, Bryan E., Jarboe, Elke A., Janat-Amsbury, Margit M., Gertz, Jason
• Format: Article
• Language: English
• Subjects: endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; estrogen receptor; Female; Genomics - methods; glucocorticoid receptor; Humans; Receptors, Glucocorticoid - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.02.076

Steroid hormone receptors are simultaneously active in many tissues and are capable of altering each other’s function. Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus, and their ligands have opposing effects on uterine growth. In endometrial tumors with high ER expression, we surprisingly found that expression of GR is associated with poor prognosis. Dexamethasone reduced normal uterine growth in vivo; however, this growth inhibition was abolished in estrogen-induced endometrial hyperplasia. We observed low genomic-binding site overlap when ER and GR are induced with their respective ligands; however, upon simultaneous induction they co-occupy more sites. GR binding is altered significantly by estradiol with GR recruited to ER-bound loci that become more accessible upon estradiol induction. Gene expression responses to co-treatment were more similar to estradiol but with additional regulated genes. Our results suggest phenotypic and molecular interplay between ER and GR in endometrial cancer. [Display omitted] •GR expression is associated with poor prognosis in ER expressing endometrial tumors•Dexamethasone inhibits normal uterine growth, but not estradiol-induced hyperplasia•Co-stimulus of ER and GR causes GR to bind ER-bound loci that are more accessible•Co-stimulus response is similar to estradiol only with some unique regulated genes Estrogen receptor α (ER) and glucocorticoid receptor (GR) are expressed in the uterus and have differential effects on growth. Vahrenkamp et al. find that expression of both receptors is associated with poor outcome in endometrial cancer and that simultaneous induction of ER and GR leads to molecular interplay between the receptors.