s-SHIP Promoter Expression Identifies Mouse Mammary Cancer Stem Cells

Stem Cell Reports. 2019 Jul 9;13(1):10-20. doi: 10.1016/j.stemcr.2019.05.013. Epub 2019 Jun 13.


During normal mammary gland development, s-SHIP promoter expression marks a distinct type of mammary stem cells, at two different stages, puberty and early mid-pregnancy. To determine whether s-SHIP is a marker of mammary cancer stem cells (CSCs), we generated bitransgenic mice by crossing the C3(1)-SV40 T-antigen transgenic mouse model of breast cancer, and a transgenic mouse (11.5kb-GFP) expressing green fluorescent protein from the s-SHIP promoter. Here we show that in mammary tumors originating in these bitransgenic mice, s-SHIP promoter expression enriches a rare cell population with CSC activity as demonstrated by sphere-forming assays in vitro and limiting dilution transplantation in vivo. These s-SHIP-positive CSCs are characterized by lower expression of Delta-like non-canonical Notch ligand 1 (DLK1), a negative regulator of the Notch pathway. Inactivation of Dlk1 in s-SHIP-negative tumor cells increases their tumorigenic potential, suggesting a role for DLK1 in mammary cancer stemness.

Keywords: CSC; DLK1; SHIP1; breast cancer; mammary tumor; notch; s-SHIP; transgenic mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / etiology*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cell Self Renewal / genetics
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Expression*
  • Genes, Reporter
  • Humans
  • Immunophenotyping
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology
  • Mice
  • Mice, Transgenic
  • Neoplastic Stem Cells / metabolism*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics*
  • Promoter Regions, Genetic*


  • Calcium-Binding Proteins
  • Dlk1 protein, mouse
  • Inpp5d protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases