Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition

J Clin Invest. 2009 Sep;119(9):2663-77. doi: 10.1172/JCI37691. Epub 2009 Aug 24.


Six1 is a developmentally regulated homeoprotein with limited expression in most normal adult tissues and frequent misexpression in a variety of malignancies. Here we demonstrate, using a bitransgenic mouse model, that misexpression of human Six1 in adult mouse mammary gland epithelium induces tumors of multiple histological subtypes in a dose-dependent manner. The neoplastic lesions induced by Six1 had an in situ origin, showed diverse differentiation, and exhibited progression to aggressive malignant neoplasms, as is often observed in human carcinoma of the breast. Strikingly, the vast majority of Six1-induced tumors underwent an epithelial-mesenchymal transition (EMT) and expressed multiple targets of activated Wnt signaling, including cyclin D1. Interestingly, Six1 and cyclin D1 coexpression was found to frequently occur in human breast cancers and was strongly predictive of poor prognosis. We further show that Six1 promoted a stem/progenitor cell phenotype in the mouse mammary gland and in Six1-driven mammary tumors. Our data thus provide genetic evidence for a potent oncogenic role for Six1 in mammary epithelial neoplasia, including promotion of EMT and stem cell-like features.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / physiopathology*
  • Cell Line, Tumor
  • Epithelium / pathology
  • Female
  • Gene Expression
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology*
  • Humans
  • Male
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / physiopathology
  • Mesoderm / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / physiopathology
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / pathology
  • Signal Transduction
  • Transforming Growth Factor beta / physiology*
  • Transplantation, Heterologous


  • Homeodomain Proteins
  • SIX1 protein, human
  • Transforming Growth Factor beta