Deregulated ephrin-B2 signaling in mammary epithelial cells alters the stem cell compartment and interferes with the epithelial differentiation pathway

Kaenel, Philip; Antonijevic, Milica; Richter, Stefanie; Küchler, Samuel; Sutter, Nora; Wotzkow Alvarez, Carlos; Strange, Robert; Andres, Anne-Catherine (2012). Deregulated ephrin-B2 signaling in mammary epithelial cells alters the stem cell compartment and interferes with the epithelial differentiation pathway. International journal of oncology, 40(2), pp. 357-69. Athens: Spandidos Publications 10.3892/ijo.2011.1238

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Unit Tiefenau Hospital (discontinued) > Forschungsgruppe Biologie und Karzinogenese der Brustdrüse (discontinued)

UniBE Contributor:

Kaenel, Philip; Wotzkow Alvarez, Carlos and Andres, Anne Catherine

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1019-6439

Publisher:

Spandidos Publications

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:21

Last Modified:

16 Jul 2014 16:33

Publisher DOI:

10.3892/ijo.2011.1238

PubMed ID:

22020958

Web of Science ID:

000298824400003

URI:

https://boris.unibe.ch/id/eprint/7005 (FactScience: 212140)

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