Loss of ERβ expression as a common step in estrogen-dependent tumor progression

Bardin, Allison J.; Boulle, Nathalie; Lazennec, Gwendal; Vignon, Françoise; Pujol, Pascal

doi:10.1677/erc.1.00800

Cited by 383 publications

(332 citation statements)

References 128 publications

Supporting

Mentioning

308

Contrasting

Unclassified

Order By: Relevance

“…Instead, decreased expression of ERb was observed in cells with forced expression of ARTN. Several reports have described loss of ERb during mammary tumorigenesis, supporting the potential role of ERb as a tumor suppressor (Park et al, 2003;Shaaban et al, 2003;Bardin et al, 2004;Rody et al, 2005). ERb has been reported to modulate ERa activity and cellular response to estrogen (Hall and McDonnel, 1999;Pettersson et al, 2000).…”

Section: Discussionmentioning

confidence: 85%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 85%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

View full text Add to dashboard Cite

show abstract

“…This correlates with the loss of ERβ preferentially in other cancers compared to normal tissue, and led to the hypothesis that ERβ is a tumor suppressor [65,66]. Some investigators have proposed that the ratio between the two subtypes is most important in determining the character of ER signaling [62].…”

Section: Erα and Erβ Expression And Activitiesmentioning

confidence: 99%

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

2008

View full text Add to dashboard Cite

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.

show abstract

“…In hormoneresponsive, ERa-positive BC cells ERb inhibits estrogen-mediated cell proliferation by increasing the expression of growth-inhibitory genes and by interfering with activation of cell cycle and anti-apoptotic genes by ERa in response to 17b-estradiol (E2: Chang et al, 2006;Grober et al, 2011). ERb is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease (Sugiura et al, 2007), is a biomarker of a less aggressive clinical phenotype (Novelli et al, 2008;Shaaban et al, 2008) and its downregulation has been postulated to represent a critical stage in estrogen-dependent tumor progression (Roger et al, 2001;Bardin et al, 2004). Despite the direct relationships between estrogen and breast carcinogenesis, the divergent roles of the two ER subtypes in BC are not fully understood, mostly because they are complex, involving genomic and non-genomic actions, regulation of gene transcription and control of mRNA stability and translation efficiency.…”

Section: Introductionmentioning

confidence: 99%

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer

et al. 2012

View full text Add to dashboard Cite

Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERa and ERb, transcription factors that display functional antagonism with each other, with ERb acting as oncosuppressor and interfering with the effects of ERa on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERa þ BC cells often lack ERb, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERb might influence BC cell behavior via miRNAs, we compared miRNome expression in ERb þ vs ERbÀ hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERb in BC cells, clearly distinguishes ERb þ , node-negative, from ERbÀ, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERb þ in BC cell nuclei. In particular, ERb downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERa on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERb in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

show abstract

Loss of ERβ expression as a common step in estrogen-dependent tumor progression

Cited by 383 publications

References 128 publications

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

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

Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer

Contact Info

Product

Resources

About