title: Ethnicity-Dependent and -Independent Heterogeneity in Healthy Normal Breast Hierarchy Impacts Tumor Characterization.
abstract: Recent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast. Ethnicity and genetic predisposition are partly responsible for this heterogeneity, evidenced by the finding that CD44+/CD24- and PROCR+/EpCAM- multi-potent stem cells were elevated significantly in African American women compared with Caucasians. ALDEFLUOR+ luminal stem/progenitor cells were lower in BRCA1-mutation carriers compared with cells from healthy donors (p = 0.0014). Moreover, tumor and adjoining-normal breast cells of the same patients showed distinct CD49f+/EpCAM+ progenitor, CD271+/EpCAM- basal, and ALDEFLUOR+ cell profiles. These inter-individual differences in the rate of differentiation in the normal breast may contribute to a substantial proportion of transcriptome, epigenome, and signaling pathway alterations and consequently has the potential to spuriously magnify the extent of documented tumor-specific gene expression. Therefore, comparative analysis of phenotypically defined subpopulations of normal and tumor cells on an individual basis may be required to identify cancer-specific aberrations.
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|VA Roudebush Medical Center, Indianapolis, IN 46202, USA.
authors: Harikrishna
authors: H
authors: Nakshatri
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Manjushree
authors: M
authors: Anjanappa
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: Poornima
authors: P
authors: Bhat-Nakshatri
mesh_terms: D001741:Black or African American / Q000235:genetics; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002452:Cell Count; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005006:Ethnicity; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006579:Heterozygote; D006801:Humans; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D010641:Phenotype; D014019:Tissue Donors
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule