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ToxSci Advance Access published online on July 21, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn141
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Influence of cellular ER{alpha}/ERβ Ratio on the ER{alpha}-Agonist Induced Proliferation of Human T47D Breast Cancer Cells

A. M. Sotoca Covaleda1,*, J. H. J. van den Berg1, J. J. M. Vervoort2, P. van der Saag3, A. Ström4, J. A. Gustafsson4, I. M. C. M. Rietjens1 and A. J. Murk1

1 Toxicology section, Wageningen University, Tuinlaan 5, 6703 HE, Wageningen, The Netherlands 2 Department of Biochemistry, Wageningen University, Dreijenlaan 3, 6703 HA Wageningen, The Netherlands 3 Hubrecht Institute/NIOB, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands 4 Department of Biosciences and Nutrition, Karolinska Institute, Novum, 14186 Huddinge, Sweden

* Corresponding author. Tel.: +31-317484357. Fax: +31-317484931. Email: ana.sotoca{at}wur.nl

Received March 26, 2008; revision received June 25, 2008; accepted July 7, 2008


  Abstract

Breast cancer cells show over-expression of estrogen receptor {alpha} (ER{alpha}) relative to estrogen receptor β (ERβ) compared to normal breast tissues. This observation has lead to the hypothesis that ERβ may modulate the proliferative effect of ER{alpha}. This study investigated how variable cellular expression ratios of the estrogen receptors ER{alpha} and ERβ, modulate the effects on cell proliferation induced by ER{alpha} or ERβ agonists, respectively. Using human osteosarcoma (U2OS) ER{alpha} or ERβ reporter cells, propyl-pyrazole-triol (PPT) was shown to be a selective ER{alpha} and diarylpropionitrile (DPN) a preferential ERβ modulator. The effects of these selective estrogen receptor modulators (SERMs) and of the model compound E2 on the proliferation of T47D human breast cancer cells with tetracycline dependent expression of ERβ (T47D-ERβ), was characterised. E2-induced cell proliferation of cells in which ERβ expression was inhibited was similar to that of the T47D wild type cells, whereas this E2-induced cell proliferation was no longer observed when ERβ expression in the T47D-ERβ cells was increased. In the T47D-ERβ cell line DPN also appeared to be able to suppress cell proliferation when levels of ERβ expression were high. In the T47D-ERβ cell line PPT was unable to suppress cell proliferation at all ratios of ER{alpha}/ERβ expression, reflecting its ability to activate only ER{alpha} and not ERβ. It is concluded that effects of estrogen-like compounds on cell proliferation are dependent on the actual ER{alpha}/ERβ expression levels in these cells or tissues, and the potential of the estrogen agonists to activate ER{alpha} and/or ERβ.

Key Words: estrogen receptors; SERM; breast cancer cells; T47D-ERβinducible; ER-U2OS-Luc.


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