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

Abstract

Abstract. 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 celland 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.

The multifaceted roles of Eph/ephrin signaling in breast cancer

“…Repopulation assays revealed that the epithelial cells of mutant ephrin-B2 transgenic epithelial cells are able to repopulate epithelial-free mammary fat pads of normal recipient mice more extensively and faster than those of controls and of native ephrin-B2 transgenic mice, confirming the augmentation of stem cells. Morphologically, these outgrowths exhibited an abnormal basal/luminal compartmentalization and impaired epithelial polarization 73 . These results demonstrate that deregulated ephrin-B2 expression interferes with the regulation of the stem cell niche and leads to a shift in the binary decision pathway during progenitor cell differentiation (Fig.…”

β-Tubulin Isotype, TUBB4B, Regulates The Maintenance of Cancer Stem Cells

“…Studies conducted to identify the regulation of CSC niche in the maintenance of self-renewal and differentiation in the normal stem cell compartments have shown that generation of expression gradients of different signaling molecules, like WNT, BMP, Eph receptors, and Ephrin-B1 play a role in the intestinal crypt cell homeostasis ( 7 – 11 ). Eph receptors and Ephrins are also reported for the maintenance of other adult stem cell niches like that of mammary gland, neural, skin and prostate ( 42 – 44 ). Eph/Ephrin signaling is also shown to be involved in cancer stem cell niche maintenance in leukemia and Glioblastoma ( 45 – 47 ).…”