Epithelial and Mesenchymal Subpopulations Within Normal Basal Breast Cell Lines Exhibit Distinct Stem Cell/Progenitor Properties

• Published in: Stem cells (Dayton, Ohio) Ohio), 2012-02, Vol.30 (2), p.292-303
• Main Authors: Sarrio, David, Franklin, Chris K., Mackay, Alan, Reis-Filho, Jorge S., Isacke, Clare M.
• Format: Article
• Language: English
• Subjects: Antigens, Differentiation - metabolism; Antigens, Neoplasm - metabolism; Bone marrow; Breast cancer; Breast Neoplasms; Cell adhesion & migration; Cell Adhesion Molecules - metabolism; Cell Line; Cell Line, Tumor; Claudins - metabolism; Differentiation; Epithelial Cell Adhesion Molecule; Epithelial Cells - metabolism; Epithelial-Mesenchymal Transition; Female; Flow Cytometry; Gene Expression; Genotype & phenotype; Homeodomain Proteins - metabolism; Humans; Mammary Glands, Human - cytology; Mesenchymal Stem Cells - metabolism; Phenotype; Progenitor cells; Snail Family Transcription Factors; Spheroids, Cellular - metabolism; Stem cell plasticity; Stem Cells; Tissue-specific stem cells; Transcription Factors - metabolism; Zinc Finger E-box-Binding Homeobox 1
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.791

It has been proposed that epithelial–mesenchymal transition (EMT) in mammary epithelial cells and breast cancer cells generates stem cell features, and that the presence of EMT characteristics in claudin‐low breast tumors reveals their origin in basal stem cells. It remains to be determined, however, whether EMT is an inherent property of normal basal stem cells, and if the presence of a mesenchymal‐like phenotype is required for the maintenance of all their stem cell properties. We used nontumorigenic basal cell lines as models of normal stem cells/progenitors and demonstrate that these cell lines contain an epithelial subpopulation (“EpCAM+,” epithelial cell adhesion molecule positive [EpCAMpos]/CD49fhigh) that spontaneously generates mesenchymal‐like cells (“Fibros,” EpCAMneg/CD49fmed/low) through EMT. Importantly, stem cell/progenitor properties such as regenerative potential, high aldehyde dehydrogenase 1 activity, and formation of three‐dimensional acini‐like structures predominantly reside within EpCAM+ cells, while Fibros exhibit invasive behavior and mammosphere‐forming ability. A gene expression profiling meta‐analysis established that EpCAM+ cells show a luminal progenitor‐like expression pattern, while Fibros most closely resemble stromal fibroblasts but not stem cells. Moreover, Fibros exhibit partial myoepithelial traits and strong similarities with claudin‐low breast cancer cells. Finally, we demonstrate that Slug and Zeb1 EMT‐inducers control the progenitor and mesenchymal‐like phenotype in EpCAM+ cells and Fibros, respectively, by inhibiting luminal differentiation. In conclusion, nontumorigenic basal cell lines have intrinsic capacity for EMT, but a mesenchymal‐like phenotype does not correlate with the acquisition of global stem cell/progenitor features. Based on our findings, we propose that EMT in normal basal cells and claudin‐low breast cancers reflects aberrant/incomplete myoepithelial differentiation. STEM CELLS 2012; 30:292–303.