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

Correspondence: Dr SAW Fuqua, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, N1200 Alkek, Houston, TX, 77030, USA. E-mail: sfuqua@bcm.edu

Received 17 June 2008; Revised 13 April 2009; Accepted 16 April 2009; Published online 29 June 2009.

Abstract

We identified a somatic mutation in estrogen receptor- (ER) 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 ER. We have developed a transgenic mouse expressing the K303R mutant ER under control of the mouse mammary tumor virus (MMTV) promoter. At 4 months of age, K303R ER transgenic animals demonstrate precocious alveolar budding compared with wild-type ER transgenic mice or nontransgenic littermates. Despite these morphologic differences, K303R ER transgenic mice displayed no differences in levels of ER, progesterone receptor or proliferation at this time-point. Pregnancy or chronic estrogen plus progesterone exposure in K303R ER transgenic mice also resulted in significantly more alveolar budding, increased -casein production and dilated ducts when compared with nontransgenic littermates. To examine the effects of mutant expression on tumorigenesis, mutant ER 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 ER 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.