title: Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties.
abstract: 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 [EpCAM(pos)]/CD49f(high)) that spontaneously generates mesenchymal-like cells ("Fibros," EpCAM(neg)/CD49f(med/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.
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. david.sarrio@icr.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Sarrio
authors.forename: Chris K
authors.initials: CK
authors.lastname: Franklin
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Clare M
authors.initials: CM
authors.lastname: Isacke
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D001943:Breast Neoplasms; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D057167:Claudins / Q000378:metabolism; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D010641:Phenotype; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular / Q000378:metabolism; D013234:Stem Cells; D014157:Transcription Factors / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D057167:Claudins; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018398:Homeodomain Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1