Interaction of Glucocorticoid Receptor (GR) with Estrogen Receptor (ER) α and Activator Protein 1 (AP1) in Dexamethasone-mediated Interference of ERα Activity

Karmakar, Shilpi; Jin, Yetao; Nagaich, Akhilesh K.

doi:10.1074/jbc.m113.473819

Cited by 113 publications

(121 citation statements)

References 70 publications

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“…Studies show that Dex occupies several ER-binding regions (EBR), and little or less sites are available for E2 binding to its receptor ERa [8]. Further, with increasing the duration of exposure time of Dex to MCF-7 cells, the GR predominantly localized in the nucleus binding to ERa.…”

Section: Discussionmentioning

confidence: 99%

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Interplay of nuclear receptors (ER, PR, and GR) and their steroid hormones in MCF-7 cells

et al. 2016

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Steroid hormones and their nuclear receptors play a major role in the development and progression of breast cancer. MCF-7 cells are triple-positive breast cancer cells expressing estrogen receptor (ER), progesterone receptor (PR), and glucocorticoid receptor (GR). However, interaction and their role in expression pattern of activator protein (AP-1) transcription factors (TFs) are not completely understood. Hence, in our study, MCF-7 cells were used as an in vitro model system to study the interplay between the receptors and hormones. MCF-7 cells were treated with estradiol-17b (E2), progesterone (P4), and dexamethasone (Dex), alone or in combination, to study the proliferation of cells and expression of AP-1 genes. MTT assay results show that E2 or P4 induced the cell proliferation by more than 35 %, and Dex decreased the proliferation by 26 %. E2 and P4 are found to increase ERa by more than twofold and c-Jun, c-Fos, and Fra-1 AP-1 TFs by more than 1.7-fold, while Dex shows opposite effect of E2-or P4-induced effect as well as effect on the expression of nuclear receptors and AP-1 factors. E2 antagonist Fulvestrant (ICI 182,780) found to reduce proliferation and E2-induced expression of AP1-TFs, while P4 or Dex antagonist Mifepristone (RU486) is found to block GRmediated expression of NRs and AP-1 mRNAs. Results suggest that E2 and P4 act synergistically, and Dex acts as an antagonist of E2 and P4.

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Section: Discussionmentioning

confidence: 99%

“…However, the effect of GC depends on the E2 concentration and the expression of ERa in breast tumor cells. Studies using in vitro model system show that GC inhibits the growth of ERa-positive cells [8]. Estrogens and glucocorticoids have opposing effects on the expression of respective nuclear receptor mRNAs and specific AP-1 factors.…”

Section: Introductionmentioning

confidence: 99%

Interplay of nuclear receptors (ER, PR, and GR) and their steroid hormones in MCF-7 cells

et al. 2016

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“…Likewise, cistromic profiling of ESR1 and GR in mouse mammary epithelial cell lines revealed significant co-operation of these two NRs, through an assisted loading mechanism, in which binding of one NR facilitates chromatin remodeling thereby enabling access to DNA for the other NR (Miranda et al 2013). Another study profiling ESR1 and GR genomic localization in MCF-7 cells revealed that, although GR co-occupies several ESR1-binding sites in cells treated with both E2 and dexamethasone, GR recruitment to these sites is associated with displacement of ESR1 leading to the repression of estrogen receptor-mediated transcriptional activation of target genes (Karmakar et al 2013). Therefore, although ESR1 co-occupies many target genes with RARA as well as GR, the nature of their interaction is reported to be both co-operative and antagonistic, perhaps reflecting different time, target and cell-specific modes of co-operation between these NRs.…”

Section: Combinatorial Control Of Gene Expression By Nrs In Breast Camentioning

confidence: 99%

Emerging functional roles of nuclear receptors in breast cancer

Doan

Graham

2017

Journal of Molecular Endocrinology

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Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.

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“…In contrast to its role in TNBC, the presence of GR in ER+ luminal breast cancers predicts good outcome (Pan et al 2011). Estrogen treatment dampened GR transcriptional activity ), whereas GR directly interfered with ER function, in part via competitive binding to ERα-response elements in DNA (Karmakar et al 2013). In addition to ER and PR (or GR), other SRs (namely, AR) also likely cooperate and interact extensively (including within PELP1 complexes) as part of an emerging paradigm of how cells, including cancer cells, continuously sense and respond to their changing hormonal milieu, and PTMs to SRs and their binding partners likely figure prominently into the mechanisms involved.…”

Section: Figurementioning

confidence: 99%

Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer

Leehy

Anderson

Daniel

et al. 2016

Journal of Molecular Endocrinology

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ReviewModifications to glucocorticoid and progesterone receptors AbstractSteroid hormone receptors (SRs) are heavily posttranslationally modified by the reversible addition of a variety of molecular moieties, including phosphorylation, acetylation, methylation, SUMOylation, and ubiquitination. These rapid and dynamic modifications may be combinatorial and interact (i.e. may be sequential, complement, or oppose each other), creating a vast array of uniquely modified receptor subspecies that allow for diverse receptor behaviors that enable highly sensitive and context-dependent hormone action. For example, in response to hormone or growth factor membrane-initiated signaling events, posttranslational modifications (PTMs) to SRs alter protein-protein interactions that govern the complex process of promoter or gene-set selection coupled to transcriptional repression or activation. Unique phosphorylation events allow SRs to associate or disassociate with specific cofactors that may include pioneer factors and other tethering partners, which specify the resulting transcriptome and ultimately change cell fate. The impact of PTMs on SR action is particularly profound in the context of breast tumorigenesis, in which frequent alterations in growth factor-initiated signaling pathways occur early and act as drivers of breast cancer progression toward endocrine resistance. In this article, with primary focus on breast cancer relevance, we review the mechanisms by which PTMs, including reversible phosphorylation events, regulate the closely related SRs, glucocorticoid receptor and progesterone receptor, allowing for precise biological responses to ever-changing hormonal stimuli.

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Interaction of Glucocorticoid Receptor (GR) with Estrogen Receptor (ER) α and Activator Protein 1 (AP1) in Dexamethasone-mediated Interference of ERα Activity

Cited by 113 publications

References 70 publications

Interplay of nuclear receptors (ER, PR, and GR) and their steroid hormones in MCF-7 cells

Interplay of nuclear receptors (ER, PR, and GR) and their steroid hormones in MCF-7 cells

Emerging functional roles of nuclear receptors in breast cancer

Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer

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