Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment

Cancer Cell. 2009 Jul 7;16(1):55-66. doi: 10.1016/j.ccr.2009.05.016.


Notch1 is a proto-oncogene in several organs. In the skin, however, Notch1 deletion leads to tumor formation, suggesting that Notch1 is a "tumor suppressor" within this context. Here we demonstrate that, unlike classical tumor suppressors, Notch1 loss in epidermal keratinocytes promotes tumorigenesis non-cell autonomously by impairing skin-barrier integrity and creating a wound-like microenvironment in the skin. Using mice with a chimeric pattern of Notch1 deletion, we determined that Notch1-expressing keratinocytes in this microenvironment readily formed papillomas, showing that Notch1 was insufficient to suppress this tumor-promoting effect. Accordingly, loss of other Notch paralogues that impaired the skin barrier also predisposed Notch1-expressing skin to tumorigenesis, demonstrating that the tumor-promoting effect of Notch1 loss involves a crosstalk between barrier-defective epidermis and its stroma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Carcinogens / toxicity
  • Epidermis / pathology
  • Gene Deletion
  • Genes, Tumor Suppressor*
  • Homeodomain Proteins / genetics
  • Mice
  • Mice, Knockout
  • Receptor, Notch1 / deficiency*
  • Receptor, Notch1 / genetics
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Stromal Cells / pathology*
  • Tetradecanoylphorbol Acetate / toxicity


  • Carcinogens
  • Homeodomain Proteins
  • MSX2 protein
  • Notch1 protein, mouse
  • Receptor, Notch1
  • 9,10-Dimethyl-1,2-benzanthracene
  • Tetradecanoylphorbol Acetate