INTERNATIONAL JOURNAL OF ONCOLOGY 40: 357-369, 2012

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

PHILIP KAENEL, MILICA ANTONIJEVIC, STEFANIE RICHTER, SAMUEL KÜCHLER, NORA SUTTER, CARLOS WOTZKOW, ROBERT STRANGE and ANNE-CATHERINE ANDRES

Department of Clinical Research, University of Bern, Tiefenaustrasse 120c, CH-3004 Bern, Switzerland

Received July 28, 2011; Accepted September 1, 2011

DOI: 10.3892/ijo.2011.1238

Abstract. Cancer most probably originates from stem/progenitor Introduction cells and exhibits a similar cell hierarchy as normal tissues. Moreover, there is growing evidence that only the stem cells Carcinogenesis in the can give rise to a variety are capable of metastasis formation. We have previously shown of breast tumors which can generally be subdivided into luminal that overexpression of a dominant negative ephrin-B2 mutant and basal type. Diagnosis, prognosis and specific therapy rely interferes with mammary gland differentiation and confers a on precise classification of tumors. Considering the aggressive- metastatic phenotype to NeuT-induced mammary tumors with ness of carcinogenic diseases and their metastatic potential, it is an increase in cells with stem/progenitor characteristics. To widely supported that this can be attributed to a small subset of investigate the role of ephrin-B2 in the control of the mammary cells mainly responsible for secondary tumor formation but also stem cell niche, we analyzed the mammary stem and progenitor relapse after therapy (1). This evoked the ongoing discussion of cell populations in transgenic mice overexpressing the mutant the cancer stem cell hypothesis suggesting stem and progenitor ephrin-B2. Quantification by FACS analysis revealed a signifi- cells to be the likely targets for cell transformation in cancero- cant increase of cells in the basal/alveolar cell-, the bi-potent genesis. Morphogenesis and homeostasis of the mammary gland progenitor- and the stem cell-enriched fractions. Moreover, as well as carcinogenesis reveal differentially regulated stem the supposed precursors of estrogen receptor-positive cells and progenitor cell niches independent of the developmental were elevated in the stem cell-enriched fraction. In contrast, status of the tissue and endocrine and paracrine signaling cues the epithelium from transgenic mice overexpressing the native (2). Thus, it appears crucial to further elucidate the regulatory ephrin-B2 showed an augmentation of the luminal cell- mechanisms of the stem cell niche in order to identify path- and the bi-potent progenitor-enriched fractions. Repopulation ways which are acquired or hijacked by tumor-initiating assays revealed that the epithelial cells of truncated ephrin-B2 cells narrowing down more specific therapeutical targets. We transgenic epithelial cells have a higher regeneration capacity previously identified cells responsible for a metastatic pheno- than those of controls and of native ephrin-B2 transgenic mice, type of NeuT induced mammary tumors in mouse models with confirming the augmentation of stem cells. Morphologically, disturbed EphB4/ephrin-B2 signaling (3). Furthermore, we these outgrowths exhibited impaired basal/luminal compart- previously described morphological disturbances in mammary mentalization and epithelial polarization. These results development (4,5). In this study, we aimed to point out effects of demonstrate that deregulated ephrin-B2 expression interferes deregulated signaling involving ephrin-B2 on the regenerative with the regulation of the stem cell niche and leads to a shift of capacity of mammary epithelial cells and analyze morpho- the differentiation pathway and may thereby contribute to the logical changes to identify mechanisms by which ephrin-B2 acquisition of the metastatic phenotype long before