A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

Williams, Cecilia; Edvardsson, Karin; Lewandowski, Sebastian; Ström, Anders; Gustafsson, J

doi:10.1038/sj.onc.1210712

Cited by 224 publications

(207 citation statements)

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“…Downregulation of BCL-2 is involved in antiestrogeninduced apoptosis and depletion of BCL-2 expression enhances sensitivity of breast cancer cells to tamoxifen (Diel et al, 1999;Zhang et al, 1999;Kim et al, 2005). BCL-2 is positively associated with ERa expression (Elledge et al, 1997) whereas decreased BCL-2 expression has been observed after induction of ERb expression in T47D mammary carcinoma cells (Williams et al, 2008), concordant with our observation that ERb is decreased and BCL-2 expression is increased by forced expression of ARTN.…”

Section: Discussionsupporting

confidence: 89%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

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We have previously identified an oncogenic role of artemin (ARTN), a member of glial cell derived neurotrophic factor family of ligands, in mammary carcinoma. We herein report that ARTN is an estrogen-inducible gene. Metaanalysis of gene expression data sets showed that ARTN expression is positively correlated to estrogen receptor (ER) status in human mammary carcinoma. Furthermore, in patients with ER-positive mammary carcinoma treated with tamoxifen, high ARTN expression is significantly correlated with decreased survival. Forced expression of ARTN in ER-positive human mammary carcinoma cells increased ER transcriptional activity, promoted estrogenindependent growth and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. ARTN-stimulated resistance to tamoxifen and fulvestrant is mediated by increased BCL-2 expression. Conversely, depletion of endogenous ARTN by smallinterfering RNA or functional antagonism of ARTN by antibody enhanced the efficacy of antiestrogens. Tamoxifen decreased ARTN expression in tamoxifen-sensitive mammary carcinoma cells whereas ARTN expression was increased in tamoxifen-resistant cells and not affected by tamoxifen treatment. Antibody inhibition of ARTN in tamoxifen-resistant cells improved tamoxifen sensitivity. Functional antagonism of ARTN therefore warrants consideration as an adjuvant therapy to enhance antiestrogen efficacy in ER-positive mammary carcinoma.

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Section: Discussionsupporting

confidence: 89%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

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“…Early responsive genes have been identified whose expression may or may not remain modulated after a longer period of exposure. Considering the complexity of breast tumor, it is important to utilize different approaches to investigate the effect of estrogen on tumor proliferation [22][23][24][25]. In this respect, neoadjuvant treatment provides a unique opportunity to study molecular/genetic changes induced by therapy in breast cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer

Mello-Grand

Singh

Ghimenti

et al. 2010

Breast Cancer Res Treat

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expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer. Breast Cancer Research and Treatment, Springer Verlag, 2010, 121 (2), pp.399-411. <10.1007/s10549-010-0887-y>. CLINICAL TRIALGene expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer Abstract Aromatase inhibition (AI) is the most effective endocrine treatment for breast cancer in post-menopausal patients, but a percentage of hormone receptor-positive cancers do not benefit from such therapy: for example, about 20% of patients treated with anastrozole do not respond and it is still impossible to accurately predict sensitivity. Our main goal was to identify a robust expression signature predictive of response to neoadjuvant treatment with anastrozole in patients with ER? breast cancer. At the same time, we addressed the question of delineating treatment effects and possible mechanisms of intrinsic resistance occurring in non-responder patients. We analyzed the transcriptome of 17 tru-cut biopsies before treatment and 13 matched surgical samples after 3 months treatment with anastrozole taken from ER? breast tumors. Molecular profiles were related to clinical response data. Treatment with anastrozole was associated with a decreased expression of genes relating to cell proliferation and an increased expression of genes relating to inflammatory processes. There was also an enrichment of induction of T-cell anergy, positive regulation of androgen signalling, synaptic transmission and vesicle trafficking in non-responders, and of cell cycle inhibition and induction of immune response in responders. We identified an expression signature of 77 probes (54 genes) that predicted response in 100% of our cases. Five of them were able to accurately predict response on an independent dataset (P = 0.0056) of 52 ER? breast cancers treated with letrozole. Ten fixed independent samples from the anastrozole study were also used for RT-qPCR validations. This study suggests that a relative small number of genes analysed in a pre-treatment biopsy may identify patients likely to respond to AI neoadjuvant treatment. This may have practical utility translatable to the clinics. Furthermore, it Maurizia Mello-Grand and Vijay Singh contributed equally to the work.Electronic supplementary material The online version of this article (doi:10.1007/s10549-010-0887-y) contains supplementary material, which is available to authorized users. delineates novel mechanisms of intrinsic resistance to AI therapy that could be further investigated in order to explore circumventing treatments.

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“…In breast cancer cells, both ERs stimulate some cell cycle regulation genes such as pS2, TGFα, and p21 Cip1 , but only ERα stimulates c-myc [30]. ERβ in the absence of ligand regulates expression of many genes modulated by ERα plus E2, whereas ERβ plus E2 modulates some genes not regulated by ERα-E2 [31][32][33]. Because context plays a major role in ER responses, it is critical to evaluate the role of ERβ in model systems expressing both ER subtypes.…”

Section: Erα and Erβ Activity -Homodimers And Heterodimers A Transcrmentioning

confidence: 99%

“…Microarray analysis showed that ERβ modulates expression of many ERα-regulated genes in ER+ breast cancer cells, including TGFβ and class 3 semaphorins, which are involved in cell proliferation [40]. ERβ overexpression in ERα+ MCF7 and T47D breast cancer cells also inhibits ERα regulation of a subset of genes involved in DNA replication, cell-cycle regulation, and proliferation [32,33]. Furthermore, in ER+ breast tumor samples there was a significant inverse correlation between ERβ transcripts and several cell cycle and DNA replication genes including CDC2, CKS2, and CDC6, suggesting that ERα/ ERβ heterodimers negatively affect breast cancer proliferation [32].…”

Section: Potential Role Of Erα/erβ Heterodimers In Biological Responsmentioning

confidence: 99%

“…Overexpression of ERβ in ERα+ MCF7 and T47D breast cancer cells inhibits cell proliferation in response to E2 [33,40,70,71], in part by increasing expression of antiproliferative genes (p21 Cip1 and p27 Kip1 ) and decreasing expression of proliferative and antiapoptotic genes (cmyc, cyclin A, and cyclin D1), thus inducing G 2 cell cycle arrest [40,70]. ERβ overexpression also inhibits tumor establishment and growth as well as E2-induced tumor formation in vivo in mouse xenografts of MCF7 and T47D cells [70][71][72].…”

Section: Potential Role Of Erα/erβ Heterodimers In Biological Responsmentioning

confidence: 99%

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ERβ in breast cancer—Onlooker, passive player, or active protector?

2008

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The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

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A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

Cited by 224 publications

References 48 publications

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Gene expression profiling and prediction of response to hormonal neoadjuvant treatment with anastrozole in surgically resectable breast cancer

ERβ in breast cancer—Onlooker, passive player, or active protector?

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