Abstract

            Background
            Adult stem cells and progenitors are responsible for breast tissue regeneration. Human breast epithelial progenitors are organized in a lineage hierarchy consisting of bipotent progenitors (BPs), myoepithelial- and luminal-restricted progenitors (LRPs) where the LRP differentiation into mature luminal cells requires estrogen receptor (ER) signaling. However, the experimental evidence exploring the relationship between the BPs and LRPs has remained elusive. In this study, we report the presence of a basal-like luminal progenitor (BLP) in human breast epithelial cells.
          
          
            Methods
            Breast reduction samples were used to obtain different subsets of human breast epithelial cell based on cell surface marker expression using flow cytometry. Loss of function and gain of function studies were employed to demonstrate the role of NOTCH3 (NR3)-FRIZZLED7 (FZD7) signaling in luminal cell fate commitment.
          
          
            Results
            Our results suggest that, NR3-FZD7 signaling axis was necessary for luminal cell fate commitment. Similar to LRPs, BLPs (NR3highFZD7highCD90+MUC1−ER−) differentiate to generate NR3medFZD7medCD90−MUC1+ER+ luminal cells. Unlike LRPs however, BLP’s proliferation and differentiation potentials depend on NR3 and regulated in part by FZD7 signaling. Lastly, we show that BLPs have a higher colony-forming potential than LRPs and that they are continuously generated from the NOTCH3−FZD7low subset of the bipotent progenitors.
          
          
            Conclusion
            Our data indicate that BPs differentiate to generate basal-like luminal progenitors that in turn differentiate into LRPs. These results provide new insights into the hierarchical organization of human breast epithelial cell and how cooperation between the Notch and Wnt signaling pathways define a new progenitor cell type.