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Estrogen receptors alfa (ERα) and beta (ERβ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11

Oncogene volume 24, pages 6605–6616 (2005)Cite this article

Abstract

The mitogenic effect of 17β-estradiol (E2) on the breast is mediated by estrogen receptor alfa (ERα), hence ERα antagonists are effective in the treatment of breast cancer. The possible use of estrogen receptor beta (ERβ) as a target in treatment of breast cancer is under investigation. The mouse mammary cell line HC11 expresses both ERs and was used to study the role of the two receptors in proliferation. E2 had no effect on proliferation. The ERα-selective agonist 4,4′,4″-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) stimulated proliferation. The ERβ-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) inhibited cell growth and induced apoptosis. PPT upregulated while DPN downregulated cyclin D1 and proliferating cell nuclear antigen (PCNA). Upon inhibition of ERα expression with RNA interference, E2 caused a decrease in cyclin D1 and PCNA, and increased apoptosis. When ERβ expression was blocked, E2 induced proliferation and cells gained the capacity to grow in soft agar. In summary, in HC11 mammary epithelial cells, ERα drives proliferation in response to E2 while ERβ is growth inhibitory. The lack of effect of E2 on HC11 cell growth is the result of the combined actions of ERα (proliferation) and ERβ (apoptosis). We suggest that use of ERβ agonists will be a useful addition in treatment of breast cancer, which, at present, is only aimed at inhibition of ERα.

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Abbreviations

ERα:

estrogen receptor alfa

ERβ:

estrogen receptor beta

E2:

17β-estradiol

PPT:

4,4′,4″-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol

DPN:

2,3-bis(4-hydroxy-phenyl)-propionitrile

ERE:

estrogen response element

HS:

horse serum

PCNA:

proliferating cell nuclear antigen

RNAi:

RNA interference

siRNAs:

small inhibitory RNAs

SERMs:

selective estrogen receptor modulators

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Acknowledgements

We are grateful to Dr Margaret Warner for encouraging discussions throughout the development of the manuscript, Dr Michel Tujague for his assistance with confocal Imaging, Cissi Gardmo for help with transient transfections and Dr Katarina Pettersson, who kindly provided pCMX-YFP-mERα and pCMX-GFP-mERβ vectors. This work was supported by funds from Swedish Cancer Fund, Magnus Bergvalls Foundation and Karolinska Institutet.

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  1. Department of Medical Nutrition, Karolinska Institutet, NOVUM, Huddinge, SE-141 86, Sweden

    Luisa A Helguero, Malin Hedengran Faulds, Jan-Åke Gustafsson & Lars-Arne Haldosén

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  1. Luisa A Helguero
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  3. Jan-Åke Gustafsson
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Correspondence to Lars-Arne Haldosén.

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Helguero, L., Faulds, M., Gustafsson, JÅ. et al. Estrogen receptors alfa (ERα) and beta (ERβ) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11. Oncogene 24, 6605–6616 (2005). https://doi.org/10.1038/sj.onc.1208807

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