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Science 314 (5804): 1467-1470

Copyright © 2006 by the American Association for the Advancement of Science

Prevention of Brca1-Mediated Mammary Tumorigenesis in Mice by a Progesterone Antagonist

Aleksandra Jovanovic Poole,1,2* Ying Li,1,2* Yoon Kim,1,2 Suh-Chin J. Lin,1,2{dagger} Wen-Hwa Lee,1 Eva Y.-H. P. Lee1,2{ddagger}

Abstract: Women with mutations in the breast cancer susceptibility gene BRCA1 are predisposed to breast and ovarian cancers. Why the BRCA1 protein suppresses tumor development specifically in ovarian hormone–sensitive tissues remains unclear. We demonstrate that mammary glands of nulliparous Brca1/p53-deficient mice accumulate lateral branches and undergo extensive alveologenesis, a phenotype that occurs only during pregnancy in wild-type mice. Progesterone receptors, but not estrogen receptors, are overexpressed in the mutant mammary epithelial cells because of a defect in their degradation by the proteasome pathway. Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis. These findings reveal a tissue-specific function for the BRCA1 protein and raise the possibility that antiprogesterone treatment may be useful for breast cancerpreventioninindividuals with BRCA1 mutations.

1 Department of Biological Chemistry, University of California, Irvine, CA 92697–4037, USA.
2 Department of Developmental and Cell Biology, University of California, Irvine, CA 92697–4037, USA.

* These authors contributed equally to this work.

{dagger} Current address: Division of Developmental Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.

{ddagger} To whom correspondence should be addressed. E-mail: elee{at}uci.edu

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