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Accelerated mammary maturation and differentiation, and delayed MMTVneu-induced tumorigenesis of K303R mutant ERα transgenic mice

Oncogene volume 28, pages 3177–3187 (2009)Cite this article

Abstract

We identified a somatic mutation in estrogen receptor-α (ERα) in breast cancer causing a lysine to arginine transition (K303R) resulting in hypersensitivity to estrogen, altered associations with coactivators and corepressors and altered posttranslational modifications of ERα. We have developed a transgenic mouse expressing the K303R mutant ERα under control of the mouse mammary tumor virus (MMTV) promoter. At 4 months of age, K303R ERα transgenic animals demonstrate precocious alveolar budding compared with wild-type ERα transgenic mice or nontransgenic littermates. Despite these morphologic differences, K303R ERα transgenic mice displayed no differences in levels of ERα, progesterone receptor or proliferation at this time-point. Pregnancy or chronic estrogen plus progesterone exposure in K303R ERα transgenic mice also resulted in significantly more alveolar budding, increased β-casein production and dilated ducts when compared with nontransgenic littermates. To examine the effects of mutant expression on tumorigenesis, mutant ERα mice were crossed with FVB-MMTVneu mice and significantly delayed time to neu-mediated tumorigenesis in bigenic animals. In contrast, mutant expression did not affect carcinogen-induced tumorigenesis. Collectively, these data demonstrate that aberrant estrogenic signaling through the K303R ERα mutation may lead to precocious alveolar budding in virgin mice, and to an expedited maturation and differentiation phenotype in the mammary glands of hormonally stimulated animals.

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Acknowledgements

We thank Dr Gary Chamness for editorial assistance and Ms Robin Sample for administrative assistance. This work was supported by NIH/NCI CA72038 to SAWF, and by DAMD17-03-1-0417 to MHH.

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  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    M H Herynk, M T Lewis, T A Hopp, D Medina, A Corona-Rodriguez, Y Cui, A R Beyer & S A W Fuqua

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  1. M H Herynk
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  2. M T Lewis
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  4. D Medina
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  8. S A W Fuqua
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Correspondence to S A W Fuqua.

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Herynk, M., Lewis, M., Hopp, T. et al. Accelerated mammary maturation and differentiation, and delayed MMTVneu-induced tumorigenesis of K303R mutant ERα transgenic mice. Oncogene 28, 3177–3187 (2009). https://doi.org/10.1038/onc.2009.174

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