Putative functional characteristics of human estrogen receptor-beta isoforms

Peng, Baocheng; Lü, Biao; Leygue, Etienne; Murphy, Leigh C.

doi:10.1677/jme.0.0300013

Cited by 112 publications

(115 citation statements)

References 41 publications

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“…In contrast, ERb2/bcx lacks 61 amino acids normally found at the C-terminus of ERb1 and instead contains novel 27 amino acids that do not encode a functional AF-2 domain (Ogawa et al, 1998b). Studies in vitro have shown that ERb2/bcx-containing constructs do not bind oestradiol and that neither can they induce gene expression via oestrogen response elements (EREs) in reporter assays (Ogawa et al, 1998b;Peng et al, 2003;Sierens et al, 2004). Interest in determining whether ERb2/bcx is expressed in breast and other cancers has been fuelled by studies using transfected cells that have claimed that coexpression of ERb2/bcx with ERa results in reduced activation of ERE-containing reporter constructs (Ogawa et al, 1998b;Peng et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The situation is complicated further by the identification of a number of splice variant isoforms of the human ERb gene (Moore et al, 1998), the mRNAs for which have been detected in breast cancer tissues and breast cancer cell lines (Fuqua et al, 1999;Speirs et al, 2000;Poola et al, 2002a, b). Studies in vitro have suggested that ERb isoforms with deletions of selected exons, or with alternative splicing at the C-terminus, may act as dominant-negative inhibitors of full-length ERa and/or ERb (Ogawa et al, 1998b;Inoue et al, 2000;Peng et al, 2003).…”

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confidence: 99%

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Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

et al. 2006

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In order to elucidate the relative importance of oestrogen receptor (ER)a, ERb and an ERb variant (ERb2/bcx) in the response of breast cancers to tamoxifen, tumour levels of each receptor were assessed in 36 patients before and after 3 months of neoadjuvant treatment with tamoxifen (20 mg daily). All patients were postmenopausal women presenting with large ERa-positive breast cancers. Clinical response to treatment was assessed by tumour volume changes as determined from sequential ultrasounds and pathological response by comparison of the tumour morphology before and after treatment. Of 33 cases, 23 (70%) were classified as having a clinical response and 16 (48%) as having a response pathologically. All tumours stained positively for ERa and ERb and 15 out of 33 (45%) for ERb2/bcx. There were no significant differences in quantitative expression of any receptor between tumours that subsequently responded and that did not, whether response was assessed clinically or pathologically. Tamoxifen treatment was associated with a decrease in ERa, but an increase was the most frequent change (17 out of 33) in ERb, and no consistent change was evident in staining of the ERb2/bcx variant. In summary, ERb1 and ERb2/bcx variant protein are detected in ERa-positive breast tumours but their expression is not associated with a response to tamoxifen. Differential changes in ERa and ERb were seen with treatment.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

et al. 2006

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“…Using IHC, it has been shown that differential expression of ERbwt and ERbcx may be used as a prognostic marker in human prostate (Fujimura et al 2001). Peng et al (2003) showed that all ERb isoforms inhibited ERa transcriptional activity on an ERE, while only ERbwt had transcriptional activity of its own. It has been shown, using cDNA microarrays in MCF-7 cells stably transfected with ERbwt and ERbcx MCF-7, that these two isoforms inhibit ERa function differently (Omoto et al 2003).…”

Section: Er Isoformsmentioning

confidence: 98%

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

Bardin¹,

Boulle²,

Lazennec³

et al. 2004

Endocr Relat Cancer

386

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The characterization of estrogen receptor beta (ERb) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERb expression in cancer as compared with benign tumors or normal tissues, whereas ERa expression persists. The loss of ERb expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERa target genes by ERb or ERb-specific gene induction could explain that ERb has a differential effect on proliferation as compared with ERa. ERb may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERa and ERb expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

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“…ERb is expressed in both normal and neoplastic human breast tissue [3,4] but its role in either is only beginning to be understood. In animal studies, while ERa has been shown to be essential for normal mammary gland development, ERb effects are more subtle, with roles in terminal differentiation [5] and modulation of ERa activity being described [6][7][8]. In contrast to ERa, published data suggest that ERb expression declines during breast tumorigenesis [3,9].…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells

Treeck

Lattrich

Springwald

et al. 2009

Breast Cancer Res Treat

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Estrogen receptor b (ERb) is widely expressed in mammary epithelium. ERb expression is reported to decline during carcinogenesis of the breast and other tissues. In this study, we examined the consequences of a loss of ERb expression in mammary epithelial cells. We knocked down ERb transcript levels in human mammary epithelial MCF-10A cells and in MCF-7 breast cancer cells by means of stable transfection with a specific shRNA plasmid. ERb knockdown resulted in a significant growth increase of both cell types in a ligand-independent manner. This effect was accompanied by elevated cyclin A2 expression in MCF-10A cells and by decreased expression of growth-inhibitory p21/ WAF and epithelial cell marker cytokeratine 8 in both cell lines. Transfection of ERb shRNA did not alter the absent proliferative estrogen response of MCF-10A cells, but conferred sensitivity to selective estrogen receptor modulator tamoxifen to this cell line. In contrast, ERb knockdown diminished estrogen responsiveness of MCF-7 breast cancer cells and also weakened the effect of tamoxifen on this cell line. These ligand-dependent effects only observed in MCF-7 cells exhibiting a high ERa/b ratio were accompanied by smaller estrogenic repression of p21/WAF expression, an impaired tamoxifen-triggered induction of this gene and by relative downregulation of ERa and cyclin A2 transcript levels. Our data suggest that ERb exerts antiproliferative effects both on MCF-10A and MCF-7 cells in a ligand-and ERa-independent manner by regulation of p21/WAF or cyclin A2 gene expression. Knockdown of ERb in both cell types was sufficient to significantly decrease transcript levels of epithelial cell marker cytokeratin 8. The results of this study support the hypothesis that ERb acts as a tumor suppressor in mammary epithelium.

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Putative functional characteristics of human estrogen receptor-beta isoforms

Cited by 112 publications

References 41 publications

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment

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

Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells

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