title: Sox2 expression in breast tumours and activation in breast cancer stem cells.
abstract: The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires self-renewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming-like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over-expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation.
authors.affiliation: Regulation of Cell Growth Laboratory, Fundación Inbiomed, San Sebastian, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Leis
authors.forename: A
authors.initials: A
authors.lastname: Eguiara
authors.forename: E
authors.initials: E
authors.lastname: Lopez-Arribillaga
authors.forename: M J
authors.initials: MJ
authors.lastname: Alberdi
authors.forename: S
authors.initials: S
authors.lastname: Hernandez-Garcia
authors.forename: K
authors.initials: K
authors.lastname: Elorriaga
authors.forename: A
authors.initials: A
authors.lastname: Pandiella
authors.forename: R
authors.initials: R
authors.lastname: Rezola
authors.forename: A G
authors.initials: AG
authors.lastname: Martin
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D018929:Cell Culture Techniques; D065150:Cellular Reprogramming; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors