¹Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

Correspondence: Professor PA Furth, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA. E-mail: paf3@georgetown.edu

²These authors contributed equally to this work.

³Current address: Department of Pharmacology and Experimental Therapeutics, University of Maryland Medical School, Baltimore, MD, USA.

⁴Current address: Medical College of Virginia Campus of Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

⁵Current address: The Jack H Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA, USA.

Received 9 January 2007; Revised 15 May 2007; Accepted 11 June 2007; Published online 23 July 2007.

Abstract

BRCA1 can regulate estrogen receptor- (ER) activity. This study tested the hypotheses that Brca1 loss in mammary epithelium alters the estrogenic growth response and that exposure to increased estrogen or ER collaborates with Brca1 deficiency to accelerate preneoplasia and cancer development. Longer ductal extension was found in mammary glands of Brca1^f/f;MMTV-Cre mice during puberty as compared to wild-type mice. Terminal end bud differentiation was impaired in Brca1 mutant mice with preservation of prolactin-induced alveolar differentiation. Exogenous estrogen stimulated an abnormal sustained increase in mammary epithelial cell proliferation and the appearance of ER-negative preneoplasia in postpubertal Brca1 mutant mice. Carcinogenesis was investigated using Brca1^f/f;MMTV-Cre mice hemizygous for p53. Exogenous estrogen increased the percentage of mice with multiple hyperplastic alveolar nodules. Targeted conditional ER overexpression in mammary epithelial cells of mice that were Brca1 mutant and hemizygous for p53 increased the percentage of mice exhibiting multiple hyperplastic nodules, invasive mammary cancers and cancer multiplicity. Significantly more than half of the preneoplasia and cancers were ER negative even as their initiation was promoted by ER overexpression.