Declining Estrogen Receptor-β Expression Defines Malignant Progression of Human Breast Neoplasia

Shaaban, Abeer M.; O'Neill, Penny; Davies, Michael; Sibson, Ross; West, Christopher R.; Smith, Paul; Foster, Christopher S.

doi:10.1097/00000478-200312000-00002

Cited by 163 publications

(157 citation statements)

References 30 publications

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“…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

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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: Discussionmentioning

confidence: 85%

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

et al. 2010

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“…Although the spectrum of mesenchymal neoplasms remains to be evaluated, ERb expression has been characterized in a number of adenocarcinomas including those of the breast, 25 ovary, [26][27][28] endometrium, 29 esophagus, 30 stomach 31 and colon. 31,32 Interestingly, in breast, 25 ovary 25-28 and endometrium, 29 malignancy is associated with loss of ERb expression while in adenocarcinoma of the esophagus 30 increased expression is seen.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

et al. 2004

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The importance of estrogen in vascular neoplasia is suggested by a predilection for women and a tendency for rapid growth during pregnancy. Although early experiments using radioligand assays demonstrated estrogen receptor (ER) expression, these findings were not confirmed by subsequent immunohistochemical studies which were performed with antibodies raised against ERa. A newly discovered estrogen receptor subtype, ERb, has not been previously characterized in vascular lesions. In order to verify the expression of estrogen receptors in vascular neoplasms as well as to clarify the inconsistency between radioligand and early immunohistochemical studies, we examined a series of 53 benign and malignant vascular neoplasms for ERb expression. All of the subtypes of vascular neoplasia examined had nuclear expression of ERb. The majority of cases (94%) displayed 2 þ to 3 þ staining. The discrepancy between radioligand studies and previous immunohistochemical studies is attributable to the use of antibodies raised against ERa, which is not expressed in vascular lesions, and not ERb, which is broadly expressed in both benign and malignant vascular neoplasms. Although ERb may be of limited diagnostic use in vascular neoplasia due to its broad expression, the potential exists for a therapeutic approach using ER agonists. The role of estrogen in vascular neoplasia has long been suspected due to the observation that vascular neoplasms tend to grow rapidly during pregnancy and in adolescence. 1 These clinical observations were initially substantiated by early experiments in the 1980s using radioligand assays, which confirmed the presence of the estrogen receptor (ER) in vascular tumors; 2,3 however, with the advent of immunohistochemical techniques, subsequent studies performed in the 1990s with antibodies raised against the ER refuted these earlier data and it appeared that the newer technology had exposed the limitations of the older biochemical assays. [4][5][6][7] Recently, an additional ER subtype, estrogen receptor beta (ERb), 8 was identified and the previous ER against which the original antibodies were raised was renamed estrogen receptor alpha (ERa). Although ERa has been assessed immunohistochemically in vascular neoplasms and found to be absent, ERb has not been previously characterized in these entities. In order to verify the expression of ER in vascular tumors as well as to clarify the inconsistency between radioligand and early immunohistochemical studies, we examined a series of 53 benign and malignant vascular neoplasms for ERb expression. Materials and methodsIn all, 22 cases of angiosarcoma, three cases of Kaposi sarcoma, one case of epithelioid hemangioendothelioma, two cases of spindle-cell hemangioma, four cases of infantile hemangioendothelioma, 13 cases of hemangioma, seven cases of lymphangioma and one case of papillary endothelial hyperplasia were identified and retrieved from the paraffin archives of the University of Chicago. Formalin-fixed paraffin-embedded specimens were cut into 4-mm sections an...

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“…Whereas ERα expression increases during breast tumorigenesis, ERβ decreases [61,85,99]. ERβ protein expression decreases significantly from normal breast tissue through ductal hyperplasia and DCIS to invasive cancer [99], and is reduced in proliferative preinvasive mammary tumors [61].…”

Section: Clinical Correlations Between Erβ Expression Proliferationmentioning

confidence: 99%

“…ERβ protein expression decreases significantly from normal breast tissue through ductal hyperplasia and DCIS to invasive cancer [99], and is reduced in proliferative preinvasive mammary tumors [61]. Increased ERβ promoter methylation, indicative of lower gene expression, was noted in premalignant lesions as well as in two-thirds of invasive breast cancer, and corresponds with poor clinical prognosis [64].…”

Section: Clinical Correlations Between Erβ Expression Proliferationmentioning

confidence: 99%

“…ERβcx protein levels, which in general are more highly expressed in breast cancer tissue versus normal tissue, significantly increase from normal glands to DCIS and invasive cancer [80,108]. Since ERβ and ERβcx are still frequently expressed in ERα-invasive breast tumors [79,87,99,109], they may be potential therapeutic targets in these cancers. A few studies have shown that ERβcx protein expression does not correlate with tumor size, histological grade, or lymph node status [18,83,110].…”

Section: Clinical Correlations Between Erβ Expression Proliferationmentioning

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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Declining Estrogen Receptor-β Expression Defines Malignant Progression of Human Breast Neoplasia

Cited by 163 publications

References 30 publications

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Estrogen receptor β expression in vascular neoplasia: an analysis of 53 benign and malignant cases

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

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