Glucocorticoid Receptor:MegaTrans Switching Mediates the Repression of an ERα-Regulated Transcriptional Program

Abstract

Summary The molecular mechanisms underlying the opposing functions of glucocorticoid receptors (GR) and estrogen receptor α (ERα) in breast cancer development remain poorly understood. Here, we report that in breast cancer cells liganded GR represses a large ERα-activated transcriptional program by binding, in trans, to ERα-occupied enhancers. This abolishes effective activation of these enhancers and their cognate target genes, and leads to inhibition of ERα-dependent binding of components of the MegaTrans complex. Consistent with the effects of SUMOylation on other classes of nuclear receptors, dexamethasone (Dex)-induced trans-repression of the estrogen (E2) program appears to depend on GR SUMOylation, which leads to stable trans-recruitment of the GR-NCoR/SMRT-HDAC3 co-repressor complex on these enhancers. Together, these results uncover a mechanism by which competitive recruitment of DNA-binding nuclear receptors/transcription factors in trans to “hot spot” enhancers serves as an effective biological strategy for trans-repression with clear implications for breast cancer and other diseases.

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

“…A significant fraction of these additional genes are differentially expressed in ER high-GR high endometrial tumors, indicating that many genes are regulated by the combination of ER and GR generally in endometrial cancer. Unlike a recent report in breast cancer (Yang et al, 2017), GR does not appear to repress an E2 transcriptional response in endometrial cancer cells. Overall, approximately one-fifth of genes affected by any treatment exhibited an unexpected gene expression level after double induction as determined by significant interaction terms in a linear model.…”

“…In addition, ER and GR have been shown to both cooperate with (Bolt et al, 2013) and compete (Karmakar et al, 2013; Meyer et al, 1989) for co-factors in breast cancer cells. GR also has been implicated in trans -repression of ER-regulated gene expression in breast cancer (Yang et al, 2017). Estrogens and corticosteroids can elicit opposite phenotypic effects in other tissues as well (Haynes et al, 2003; Lam et al, 1996; Terakawa et al, 1985), including the uterus (Gunin et al, 2001; Markaverich et al, 1981; Rabin et al, 1990; Rhen et al, 2003).…”

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

“…A significant fraction of these additional genes are also differentially expressed in ER high-GR high endometrial tumors, indicating that many genes are regulated by the combination of ER and GR generally in endometrial cancer. Unlike a recent report in breast cancer (Yang et al, 2017), GR does not appear to repress an E2 transcriptional response in endometrial cancer cells. Overall, about one-fifth of genes affected by any treatment exhibited an unexpected gene expression level after double induction as determined by significant interaction terms in a linear model.…”

“…In addition, ER and GR have been shown to both cooperate (Bolt et al, 2013) and compete (Karmakar et al, 2013;Meyer et al, 1989) for cofactors in breast cancer cells. GR has also been implicated in trans-repression of ER regulated gene expression in breast cancer (Yang et al, 2017). Estrogens and corticosteroids can elicit opposite phenotypic effects in other tissues as well (Haynes et al, 2003;Lam et al, 1996;Terakawa et al, 1985), including the uterus (Gunin et al, 2001;Markaverich et al, 1981;Rabin et al, 1990;Rhen et al, 2003).…”

Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery

“…Informative in this regard are the results of a previous study demonstrating, in cellular models of endocrine-therapy-resistant prostate cancer, that phosphorylation of the transcriptional coregulator EZH2 shifted its binding partner preference from PRC1 to androgen receptor (AR), which resulted in a significant change in the AR-cistrome (Xu et al, 2012). Further, it has been shown that the ERa cistrome can be altered by activating other nuclear receptors (e.g., progesterone, glucocorticoid, androgen, or retinoic acid receptors) (Mohammed et al, 2015;Yang et al, 2017). When taken together, it seems likely that the binding partner preferences of WT and mutant ERa will be different and that these differences may explain the alterations in the chromatin-binding landscape noted.…”