Oncogene (2005) 24, 3554−3562. doi: 10.1038/sj.onc.1208426 Published online 7 March 2005
Published online 07 March 2005
Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer
Laundette P Jones1, Minglin Li1, Ewa D Halama1, Yongxian Ma1, Ronald Lubet2, Clinton J Grubbs3, Chu-Xia Deng4, Eliot M Rosen1 and Priscilla A Furth1
1. 1Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA
2. 2National Cancer Institute, Division of Chemoprevention, Bethesda, MD, USA
3. 3Chemoprevention Center, University of Alabama at Birmingham, Birmingham, AL, USA
4. 4National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Correspondence: PA Furth, Georgetown University, Research Building Room E520A, 3970 Reservoir Road, Washington, DC 20057, USA
Received 20 July 2004; Revised 01 November 2004; Accepted 01 December 2004; Published online 07 March 2005.
Loss of full-length Brca1 in mammary epithelial cells of the mouse mammary tumor virus (MMTV)-Cre Brca1 conditional exon 11 deletion mouse model results in the development of mammary adenocarcinomas with similar genetic changes to those found in human BRCA1-mutation-related breast cancers. We used this experimental model to evaluate the chemopreventive effect of tamoxifen on the development of mammary preneoplasia and adenocarcinoma. No protective effects of tamoxifen administration on mammary cancer development were found. Instead, tamoxifen treatment significantly increased rates of mammary epithelial cell proliferation and the prevalence of mammary hyperplasia at 6 months of age. Tamoxifen-exposed mice developed adenocarcinomas at younger ages than control mice and a higher percentage of mice developed adenocarcinomas by 12 months of age. Both whole mouse and tissue culture cell models were used to test if loss of full-length Brca1 was associated with a relative increase in the agonist activity of tamoxifen. Tamoxifen induced increased ductal growth in MMTV-Cre Brca1 conditional mice compared to wild type. Estrogen receptor alpha (ERalpha) expression was downregulated in the tamoxifen-induced hyperplasias. Reducing BRCA1 levels in MCF-7 cells using siRNA resulted in a relative increase in the agonist activity of tamoxifen. Results suggest a model of mammary cancer progression in which loss of full-length Brca1 altered the agonist/antagonist activity of tamoxifen, resulting in tamoxifen-induced mammary epithelial cell proliferation with subsequent loss of ERalpha expression and development of ERalpha-negative hyperplasias and adenocarcinomas.