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PMID: 14521515 Published · ppublish English Journal Article Review

Regulation of human breast epithelial stem cells.

Cell proliferation ·Vol. 36 Suppl 1 ·2003-10-00 ·Pages 45-58

Clarke RB, Anderson E, Howell A, Potten CS

Abstract

Breast epithelial stem cells are thought to be the primary targets in the aetiology of breast cancer. As breast cancers are predominantly oestrogen and progesterone receptor-positive (ERalpha/PR+), we investigated the biology of ERalpha/PR+ cells and their relationship to stem cells in normal human breast epithelium. Several complementary approaches were used to characterize the stem-cell population and relate it to ERalpha/PR+ cells, including dual label colocalization on tissue sections, isolation of a Hoechst dye-effluxing 'side population' using flow cytometry, and examination of DNA label retention. The intermediate or suprabasal population suggested by others to be breast stem cells comprises ERalpha/PR+ cells that coexpress the putative stem-cell markers including cytokeratin 19. Human breast epithelial cells with Hoechst dye-effluxing 'side population' properties characteristic of mammary stem cells in mice were demonstrated by lack of expression of myoepithelial and luminal cell-specific antigens such as CALLA and MUC1 to be undifferentiated cells. Using DNA radiolabelling of human tissue implanted into athymic nude mice, a population of label-retaining putative stem cells (LRC) were shown to be enriched for cells expressing the putative stem-cell markers p21CIP1/WAF1 and Musashi-1, which, interestingly, were expressed in separate subpopulations of ERalpha/PR+ cells. Finally, expression patterns of Musashi-1 and Notch-1 in relation to ERalpha/PR+ and adjacent proliferating cells suggest that the evolutionarily conserved Delta/Notch signalling pathway regulates asymmetric division of the putative stem-cell population. The data suggest a model in which ERalpha/PR+ cells scattered through the epithelium are stem cells that self-renew through asymmetric cell division and generate patches of transit amplifying and differentiated cells. ERalpha/PR+ breast cancers exhibit loss of the two key regulators of asymmetric cell division, Musashi-1 and Notch-1 and thus may arise from symmetric division of the ERalpha/PR+ stem cell.

MeSH Terms
Breast/cytology Epithelial Cells/cytology,physiology Humans Stem Cells/cytology,physiology
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Clarke Robert B
Breast Biology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Withington, Manchester, UK. rclarke@picr.man.ac.uk
Anderson Elizabeth
Howell Anthony
Potten Christopher S
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Article Info
Journal
Cell proliferation
Abbr.
Cell Prolif
ISSN
0960-7722
DOI
10.1046/j.1365-2184.36.s.1.5.x
Email
rclarke@picr.man.ac.uk
Published
2003-10-00
Pages
45-58
Language
English
Region
England
NLM ID
9105195
PMCID
PMC6495733
Subset
IM
External Links
PubMed source DOI: 10.1046/j.1365-2184.36.s.1.5.x PMC Full Text View journal details
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