Deregulated ephrin-B2 signaling in mammary epithelial cells alters the             stem cell compartment and interferes with the epithelial differentiation pathway.
Cancer most probably originates from stem/progenitor cells and exhibits             a similar cell hierarchy as normal tissues. Moreover, there is growing evidence             that only the stem cells are capable of metastasis formation. We have previously             shown that overexpression of a dominant negative ephrin-B2 mutant interferes with             mammary gland differentiation and confers a metastatic phenotype to NeuT-induced             mammary tumors with an increase in cells with stem/progenitor characteristics.             To investigate the role of ephrin-B2 in the control of the mammary stem cell niche,             we analyzed the mammary stem and progenitor cell populations in transgenic mice             overexpressing the mutant ephrin-B2. Quantification by FACS analysis revealed             a significant increase of cells in the basal/alveolar cell-, the bi-potent progenitor-             and the stem cell-enriched fractions. Moreover, the supposed precursors of estrogen             receptor-positive cells were elevated in the stem cell-enriched fraction. In contrast,             the epithelium from transgenic mice overexpressing the native ephrin-B2 gene showed             an augmentation of the luminal cell- and the bi-potent progenitor-enriched fractions.             Repopulation assays revealed that the epithelial cells of truncated ephrin-B2             transgenic epithelial cells have a higher regeneration capacity than those of             controls and of native ephrin-B2 transgenic mice, confirming the augmentation             of stem cells. Morphologically, these outgrowths exhibited impaired basal/luminal             compartmentalization and epithelial polarization. These results demonstrate that             deregulated ephrin-B2 expression interferes with the regulation of the stem cell             niche and leads to a shift of the differentiation pathway and may thereby contribute             to the acquisition of the metastatic phenotype long before carcinogenic growth             becomes apparent.
Department of Clinical Research, University of Bern, Tiefenaustrasse                     120c, CH-3004 Bern, Switzerland.
Philip
P
Kaenel
Milica
M
Antonijevic
Stefanie
S
Richter
Samuel
S
Küchler
Nora
N
Sutter
Carlos
C
Wotzkow
Robert
R
Strange
Anne-Catherine
AC
Andres
D048868:Adaptor Proteins, Signal Transducing; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000637:transplantation; D005260:Female; D006706:Homeostasis; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D062826:Zonula Occludens-1 Protein
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D036388:Ephrin-B2; D008565:Membrane Proteins; C115084:Pard3 protein, mouse; D010750:Phosphoproteins; D011960:Receptors, Estrogen; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein