Distinct Roles of Unliganded and Liganded Estrogen Receptors in Transcriptional Repression

Čvoro, Aleksandra; Tzagarakis-Foster, Christina; Tatomer, Deirdre C.; Paruthiyil, Sreenivasan; Fox, Mark S.; Leitman, Dale C.

doi:10.1016/j.molcel.2006.01.014

Cited by 152 publications

(140 citation statements)

References 56 publications

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“…Ligand-independent functions of ERα have been described in several tissues in addition to breast cancer cells (2)(3)(4)(5). Results reported here provide a frame to understand why ERα is required to respond to aromatase inhibitors in breast cancer.…”

Section: Significancementioning

confidence: 71%

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Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

Caizzi

Ferrero

Cutrupi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Estrogen receptor-α (ERα) has central role in hormone-dependent breast cancer and its ligand-induced functions have been extensively characterized. However, evidence exists that ERα has functions that are independent of ligands. In the present work, we investigated the binding of ERα to chromatin in the absence of ligands and its functions on gene regulation. We demonstrated that in MCF7 breast cancer cells unliganded ERα binds to more than 4,000 chromatin sites. Unexpectedly, although almost entirely comprised in the larger group of estrogen-induced binding sites, we found that unliganded-ERα binding is specifically linked to genes with developmental functions, compared with estrogen-induced binding. Moreover, we found that siRNA-mediated down-regulation of ERα in absence of estrogen is accompanied by changes in the expression levels of hundreds of coding and noncoding RNAs. Down-regulated mRNAs showed enrichment in genes related to epithelial cell growth and development. Stable ERα down-regulation using shRNA, which caused cell growth arrest, was accompanied by increased H3K27me3 at ERα binding sites. Finally, we found that FOXA1 and AP2γ binding to several sites is decreased upon ERα silencing, suggesting that unliganded ERα participates, together with other factors, in the maintenance of the luminal-specific cistrome in breast cancer cells.

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Section: Significancementioning

confidence: 71%

“…2 and references therein). Ligand-independent activity of ERα was reported by several groups on individual genes (3)(4)(5). Genomewide ERα binding in the absence of estrogen was also described in breast cancer cells acquainted with growing in hormonedepleted media (6)(7)(8) and in mouse uterus (9).…”

mentioning

confidence: 89%

Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

Caizzi

Ferrero

Cutrupi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…24 A second hypothesis is that estrogen leads to the recruitment of GRIP1, which acts as a co-repressor on the TNFα promoter. 25 Alternatively, ERα has also been shown to sequester coactivators from NFκB 26 to prevent transcription of the cytokines. Other possibilities include the ability of ERα to inhibit IKK activity or degradation of IkB, thereby preventing NFκB transcriptional activation.…”

Section: The Regulation Of Osteoclastogenic Cytokines By Estrogenmentioning

confidence: 99%

Unraveling estrogen action in osteoporosis

Krum

Brown

2008

Cell Cycle

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A decrease in estrogen levels at menopause leads to a rapid loss of bone mineral density and an increase in fracture risk. For over ten years it has been known that the beneficial effects of estrogen are due in part to the ability of estrogen to suppress osteoclastogenic cytokine production in T-cells and osteoblasts. In addition to suppressing these cytokines, estrogen has been shown to induce the apoptotic death of osteoclasts. A variety of different mechanisms have been suggested to explain the estrogen regulation of osteoclast survival. One hypothesis is that estrogen, via rapid non-genomic signaling, induces apoptosis without the need for direct binding of estrogen receptor α (ERα) to DNA. A second hypothesis proposes that estrogen-stimulation of ERα in osteoclasts induces the expression of Fas Ligand which in turn leads to cell death via an autocrine mechanism. In contrast, recent work from our lab has led to a genomic model of estrogen action in which estrogen acts to induce ERα binding to transcriptional enhancers in the Fas Ligand gene leading to its upregulation in osteoblasts which through a paracrine mechanism induces apoptosis in osteoclasts. Here we will focus on these differing models of the mechanism of estrogen-mediated osteoclast apoptosis.

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“…The observation that ERa is able to bind to this region in the absence of estrogen stimulation by ChIP analysis revealed that LRP16 is a primary target of ERa. Similarly, estrogen-repressed cyclin G2, tumour necrosis factor a (TNFa) and E-cadherin genes are also ERa primary target genes (Oesterreich et al 2003, Cvoro et al 2006, Stossi et al 2006. Similar to the binding of unliganded ERa to the promoter region of LRP16 gene, the unliganded ERa can bind to the AP1/NF-kB element of TNFa promoter region and enhance its transcription; however, it will be removed from TNFa promoter region as in the case of LRP16 gene after estrogen treatment (Cvoro et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, estrogen-repressed cyclin G2, tumour necrosis factor a (TNFa) and E-cadherin genes are also ERa primary target genes (Oesterreich et al 2003, Cvoro et al 2006, Stossi et al 2006. Similar to the binding of unliganded ERa to the promoter region of LRP16 gene, the unliganded ERa can bind to the AP1/NF-kB element of TNFa promoter region and enhance its transcription; however, it will be removed from TNFa promoter region as in the case of LRP16 gene after estrogen treatment (Cvoro et al 2006). Unliganded ERa can enhance cyclin G2 transcription by binding to a 1/2 ERE/Sp1 site within its promoter, or enhance E-cadherin transcription by binding to the most proximal region of its promoter, which does not contain any classical ERE but three E-boxes.…”

Section: Discussionmentioning

confidence: 99%

Differential induction of LRP16 by liganded and unliganded estrogen receptor α in SKOV3 ovarian carcinoma cells

Tian

Wu²,

Zhao³

et al. 2009

Journal of Endocrinology

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Previously, we investigated the induction effect of LRP16 expression by estrogen (17b-estradiol, E 2 ) and established a feed-forward mechanism that activated estrogen receptor a (ERa) transactivation in estrogen-dependent epithelial cancer cells. LRP16 is required for ERa signaling transduction by functioning as an ERa coactivator. In this study, we demonstrated that LRP16 expression was upregulated in E 2 -responsive BG-1 ovarian cancer cells, but was downregulated in estrogen-resistant SKOV3 ovarian cancer cells. Pure estrogen antagonist ICI 182 780 did not affect LRP16 expression in SKOV3 cell. The unliganded ERa upregulated LRP16 expression and enhanced LRP16 promoter activity in SKOV3 cells; however, this induction was blocked by estrogen stimulation. Results from chromatin immunoprecipitation experiment revealed a strong recruitment of the unliganded ERa at LRP16 promoter in the absence of estrogen; however, ERa was largely released from the DNA upon E 2 stimulation. Modulation in LRP16 expression level did not significantly change the proliferation rate of SKOV3 cells and the growth responsiveness of cells to E 2 . Knockdown of LRP16 by RNA interference in SKOV3 cells markedly attenuated estrogen response elementdependent ERa reporter gene activity and E 2 -induced c-Myc expression. Our study suggests a novel mechanism of estrogen resistance of ovarian cancer by which estrogenrepressed signaling pathway antagonizes estrogen-activated signaling transduction.

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Distinct Roles of Unliganded and Liganded Estrogen Receptors in Transcriptional Repression

Cited by 152 publications

References 56 publications

Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

Genome-wide activity of unliganded estrogen receptor-α in breast cancer cells

Unraveling estrogen action in osteoporosis

Differential induction of LRP16 by liganded and unliganded estrogen receptor α in SKOV3 ovarian carcinoma cells

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