title: Sequencing of breast cancer stem cell populations indicates a dynamic conversion between differentiation states in vivo.
abstract: BACKGROUND
  The cancer stem cell model implies a hierarchical organization within breast tumors maintained by cancer stem-like cells (CSCs). Accordingly, CSCs are a subpopulation of cancer cells with capacity for self-renewal, differentiation and tumor initiation. These cells can be isolated through the phenotypic markers CD44+/CD24-, expression of ALDH1 and an ability to form nonadherent, multicellular spheres in vitro. However, controversies to describe the stem cell model exist; it is unclear whether the tumorigenicity of CSCs in vivo is solely a proxy for a certain genotype. Moreover, in vivo evidence is lacking to fully define the reversibility of CSC differentiation.
  
  
  METHODS
  In order to answer these questions, we undertook exome sequencing of CSCs from 12 breast cancer patients, along with paired primary tumor samples. As suggested by stem classical cell biology, we assumed that the number of mutations in the CSC subpopulation should be lower and distinct compared to the differentiated tumor cells with higher proliferation.
  
  
  RESULTS
  Our analysis revealed that the majority of somatic mutations are shared between CSCs and bulk primary tumor, with similar frequencies in the two.
  
  
  CONCLUSIONS
  The data presented here exclude the possibility that CSCs are only a phenotypic consequence of certain somatic mutations, that is a distinct and non-reversible population of cells. In addition, our results imply that CSCs must be a population of cells that can dynamically switch from differentiated tumor cells, and vice versa. This finding increases our understanding of CSC function in tumor heterogeneity and the importance of identifying drugs to counter de-differentiation rather than targeting CSCs.
authors.forename: Daniel
authors.initials: D
authors.lastname: Klevebring
authors.forename: Gustaf
authors.initials: G
authors.lastname: Rosin
authors.forename: Ran
authors.initials: R
authors.lastname: Ma
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Irma
authors.initials: I
authors.lastname: Fredriksson
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
authors.forename: Johan
authors.initials: J
authors.lastname: Hartman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D059472:Exome; D005260:Female; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016130:Immunophenotyping; D009154:Mutation; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010641:Phenotype