Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer.
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.
Jones
Laundette P
LP
Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
Li
Minglin
M
Halama
Ewa D
ED
Ma
Yongxian
Y
Lubet
Ronald
R
Grubbs
Clinton J
CJ
Deng
Chu-Xia
CX
Rosen
Eliot M
EM
Furth
Priscilla A
PA
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000187:drug effects*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000187:drug effects; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D015151:Immunoblotting; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000009:adverse effects*
D018931:Antineoplastic Agents, Hormonal; D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D013629:Tamoxifen