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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
BRCA1 regulates human mammary stem/progenitor cell fate

Suling Liu^*, Christophe Ginestier^*, Emmanuelle Charafe-Jauffret, Hailey Foco^*, Celina G. Kleer^*, Sofia D. Merajver^*, Gabriela Dontu^*, and Max S. Wicha^*,

*Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, Unité Mixte de Recherche 599, Institut National de la Santé et de la Recherche Médicale/Institut Paoli-Calmettes, 13009 Marseille, France

Communicated by David Ginsburg, University of Michigan Medical School, Ann Arbor, MI, December 11, 2007 (received for review October 23, 2007)

Although it is well established that women with germ-line mutations in the BRCA1 gene have a greatly increased lifetime incidence of breast and ovarian cancer, the molecular mechanisms responsible for this tissue-specific carcinogenesis remain undefined. The majority of these breast cancers are of the basal-like phenotype characterized by lack of expression of ER, PR, and ERBB2. Because this phenotype has been proposed to resemble that of normal breast stem cells, we examined the role of BRCA1 in human mammary stem cell fate. Using both in vitro systems and a humanized NOD/SCID mouse model, we demonstrate that BRCA1 expression is required for the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Knockdown of BRCA1 in primary breast epithelial cells leads to an increase in cells displaying the stem/progenitor cell marker ALDH1 and a decrease in cells expressing luminal epithelial markers and estrogen receptor. In breast tissues from women with germ-line BRCA1 mutations, but not normal controls, we detect entire lobules that, although histologically normal, are positive for ALDH1 expression but are negative for the expression of ER. Loss of heterozygosity for BRCA1 was documented in these ALDH1-positive lobules but not in adjacent ALDH1-negative lobules. Taken together, these studies demonstrate that BRCA1 plays a critical role in the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Because BRCA1 also plays a role in DNA repair, our work suggests that loss of BRCA1 may result in the accumulation of genetically unstable breast stem cells, providing prime targets for further carcinogenic events.

breast cancer | stem cell | hereditary cancer

Author contributions: S.L. and C.G. contributed equally to this work; S.L., C.G., and M.S.W. designed research; S.L., C.G., and H.F. performed research; C.G.K. and S.D.M. contributed new reagents/analytic tools; S.L., C.G., E.C.-J., G.D., and M.S.W. analyzed data; and S.L., C.G., G.D., and M.S.W. wrote the paper.

Conflict of interest statement: M.S.W. has financial holdings in and is a scientific advisor for OncoMed Pharmaceuticals.

This article contains supporting information online at www.pnas.org/cgi/content/full/0711613105/DC1.

To whom correspondence should be addressed. E-mail: mwicha{at}umich.edu

© 2008 by The National Academy of Sciences of the USA

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