Estrogen receptors and proliferation markers in primary and recurrent breast cancer

Jensen, Elwood V.; Cheng, Guojun; Palmieri, Carlo; Saji, Shigehira; Mäkelä, Sari; Noorden, Susan Van; Wahlström, Torsten; Warner, Margaret; Coombes, R. Charles; Gustafsson, Jan Åke

doi:10.1073/pnas.211556298

Cited by 196 publications

(178 citation statements)

References 30 publications

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“…In invasive breast tumors from postmenopausal women, there was a trend for ERb expression to increased cell proliferation and worse prognosis (O'Neill et al 2004). ERb expression was also found to be associated with increased expression of cell proliferation markers Ki67 and cyclin A in human breast cancers (Jensen et al 2001). High intake of dietary plant estrogen has been associated with a low incidence of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Roles of estrogen receptor and in modulating urothelial cell proliferation

Teng¹,

Wang²,

Jarrard³

et al. 2008

Endocrine Related Cancer

108

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We reported previously that both subtypes of estrogen receptors, ERa and ERb, are expressed by human urothelial cells and mediate estrogen-induced cell proliferation in these cells. The aim of this study was to determine the extent to which each ER subtype contributes to urothelial cell proliferation and their possible involvement in the regulation of the cell cycle. We compared the expression of ERa and ERb mRNAs and protein quantitatively in primarily cultured human bladder urothelial cells obtained from six individuals with three immortalized urothelial (E6, E7, and UROtsa) and two bladder cancer cell lines (HTB-9 and T24). We found that all these cells express similar levels of ERb, but immortalized and cancer cells express much higher amounts of ERa than primary cells. Higher levels of ERa mRNA were also observed in the biopsies of bladder transitional cell carcinoma compared with sample from the same bladder unaffected by tumor. Using the ERaselective agonist PPT, the ERb-selective agonist DPN, and specific small interfering RNA against ERa or ERb, we found that ERb predominantly mediates estrogen-induced G1/S transition and cell proliferation in the primary urothelial cells. By contrast, ERa predominantly mediates estrogeninduced G1/S transition and cell proliferation in bladder cancer cell lines. Furthermore, we found that 17b-estradiol (E 2 ) rapidly induces phosphorylation of extracellular signal-regulated kinases, but U0126, a mitogen-activated protein kinase kinase (MEK) inhibitor, does not affect E 2 -induced urothelial cell proliferation. E 2 up-regulated cyclin D1 and cyclin E expression in both the primary and bladder cancer cells, and the cancer cells have higher cyclin D1 and cyclin E expression during G0/G1 phases. Our data suggest that estrogen exerts its effects through different ER subtypes in urothelial cells. Increased expression of ERa may contribute to early induction of cyclin D1 and cyclin E during the cell cycle in bladder cancer cells.

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Section: Discussionmentioning

confidence: 99%

Roles of estrogen receptor and in modulating urothelial cell proliferation

Teng¹,

Wang²,

Jarrard³

et al. 2008

Endocrine Related Cancer

108

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“…Down-regulation of ER␤ by tamoxifen would eliminate this unwanted effect. We have previously reported that there is an up-regulation of ER␤ in tamoxifenresistant breast cancer (28). If ER␤ is responsible for tamoxifen-mediated proliferation in tamoxifen-resistant breast cancer, this may be one condition where an ER␤ antagonist may be of clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

“…In both rodent and human mammary glands, the dominant ER in the stroma is ER␤, not ER␣ (3,4,7,27,28), indicating that E 2 -stimulated growth factor release from the stroma is very likely ER␤-mediated. This finding is surprising for two reasons: (i) the overwhelming evidence that ER␣ is the receptor controlling E 2 -mediated proliferation, and (ii) the apparently normal development of the mammary gland in ER␤ Ϫ͞Ϫ mice.…”

mentioning

confidence: 99%

Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland

Cheng

Zhang

Warner

et al. 2004

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

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128

111

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Most evidence supports the view that ERα is responsible for estrogen (ovarian estradiol, E 2 )-induced proliferation in the epithelial cells of the mammary gland, but despite this, proliferating epithelial cells do not express ERα. We have examined this apparent paradox by studying the role of ERα and ERβ in E 2 -induced proliferation in mammary glands (measured by BrdUrd incorporation into DNA) in mice with intact ERβ (WT mice) and those in which the ERβ gene has been inactivated (ERβ -/- mice). On treatment of ERβ -/- mice with E 2 or ovariectomized WT mice with E 2 , tamoxifen, or a specific ERβ agonist (BAG), the number of BrdUrd-labeled cells in mammary glands increased from 3.4% in controls to 28-38% in the treated mice. This indicates that both ERα and ERβ can mediate E 2 -induced proliferation independently of each other. With specific antibodies, ERβ was found in both epithelial and stromal cells, whereas ERα was strictly epithelial. Within 4 h of a single dose of E 2 , ERα was lost from the nuclei of epithelial cells. In WT mice, ERα reappeared by 24 h, but in ERβ -/- mice, return to the nucleus was delayed by 24 h. At 4 h after E 2 , neither ERα nor progesterone receptor was detectable in BrdUrd-labeled nuclei but by 48 h after E 2 , 29% of the BrdUrd-labeled cells expressed ERα, and 21-38% expressed progesterone receptor. During 3 weeks of continuous E 2 treatment, ERβ remained in the nucleus, but there was no detectable ERα. With tamoxifen treatment, ERα remained in the nucleus, but ERβ was lost. From these results, we conclude that ERα receives the proliferation signal from E 2 , initiates DNA synthesis, and is then lost from cells. The subsequent steps in proliferation can proceed in the absence of either ERα or ERβ. ERβ facilitates the return of ERα to the nucleus and restores responsiveness to E 2 . By down-regulating ERβ, tamoxifen may prolong refractoriness to E 2 in mammary epithelium.

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“…ERβ protein expression in breast cancer epithelium is associated with elevated levels of the proliferation markers Ki67 and Cyclin A, whereas ERα is associated with decreased levels [98,106]. Ki67 and Cyclin A were expressed at the highest levels in ERα−/ERβ+ tumors, and ERβ protein expression significantly correlated with Ki67 staining in ERα− tumors [82,87,106], suggesting that ERβ may play a role in the proliferation of ERα− breast tumors. In contrast, one group reported an inverse correlation between ERβ protein and Ki67, especially in high grade DCIS [61].…”

Section: Clinical Correlations Between Erβ Expression Proliferationmentioning

confidence: 93%

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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Estrogen receptors and proliferation markers in primary and recurrent breast cancer

Cited by 196 publications

References 30 publications

Roles of estrogen receptor and in modulating urothelial cell proliferation

Roles of estrogen receptor and in modulating urothelial cell proliferation

Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland

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

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