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Published online
doi:10.1083/jcb.200611114
The Journal of Cell Biology, Vol. 177, No. 1, 87-101
The Rockefeller University Press, 0021-9525 $30.00
© Villadsen et al.
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Article

Evidence for a stem cell hierarchy in the adult human breast



René Villadsen1, Agla J. Fridriksdottir1, Lone Rønnov-Jessen2, Thorarinn Gudjonsson3, Fritz Rank4, Mark A. LaBarge5, Mina J. Bissell5, and Ole W. Petersen1

1 Department of Cellular and Molecular Medicine, Faculty of Health Sciences, and 2 Zoophysiological Laboratory, Department of Molecular Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark
3 Molecular and Cell Biology Research Laboratory, Icelandic Cancer Society, University of Iceland, Faculty of Medicine, IS-125 Reykjavik, Iceland
4 Department of Pathology, State University Hospital, DK-2100 Copenhagen Ø, Denmark
5 Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, Berkeley, CA 94720

Correspondence to Ole W. Petersen: O.W.Petersen{at}mai.ku.dk

Cellular pathways that contribute to adult human mammary gland architecture and lineages have not been previously described. In this study, we identify a candidate stem cell niche in ducts and zones containing progenitor cells in lobules. Putative stem cells residing in ducts were essentially quiescent, whereas the progenitor cells in the lobules were more likely to be actively dividing. Cells from ducts and lobules collected under the microscope were functionally characterized by colony formation on tissue culture plastic, mammosphere formation in suspension culture, and morphogenesis in laminin-rich extracellular matrix gels. Staining for the lineage markers keratins K14 and K19 further revealed multipotent cells in the stem cell zone and three lineage-restricted cell types outside this zone. Multiparameter cell sorting and functional characterization with reference to anatomical sites in situ confirmed this pattern. The proposal that the four cell types are indeed constituents of an as of yet undescribed stem cell hierarchy was assessed in long-term cultures in which senescence was bypassed. These findings identify an adult human breast ductal stem cell activity and its earliest descendants.

R. Villadsen and A.J. Fridriksdottir contributed equally to this paper.

Abbreviations used in this paper: HPV, human papilloma virus; lrECM, laminin-rich ECM; RS, restriction site; SSEA-4, stage-specific embryonal antigen-4; TDLU, terminal duct lobular unit.


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