Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors

Oncogene. 2010 Aug 12;29(32):4543-54. doi: 10.1038/onc.2010.186. Epub 2010 Jun 21.

Abstract

Members of the Notch family are involved in the development of breast cancer in animal models and in humans. In young transgenic mice, expressing intracellular activated Notch1 (N1(IC)) in mammary cells, we found that CD24(+) CD29(high) progenitor cells had enhanced survival, and were expanded through a cyclin D1-dependent pathway. This expansion positively correlated with the later cyclin D1-dependent formation of basal-like ductal tumors. This expanded population exhibited abnormal differentiation skewed toward the basal cells, showed signs of pre-malignancy (low PTEN/p53 and high c-myc) and contained stem cells with impaired self-renewal in vivo, and more numerous multipotent, ductal-restricted progenitors. Our data suggest that N1(IC) can favor transformation of progenitor cells early in life through a cyclin D1-dependent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • CD24 Antigen / metabolism
  • Cell Culture Techniques
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cyclin D1 / deficiency
  • Cyclin D1 / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Integrin beta1 / metabolism
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / pathology*
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology*
  • Mammary Tumor Virus, Mouse / genetics
  • Mice
  • Mice, Transgenic
  • Multipotent Stem Cells / metabolism
  • Multipotent Stem Cells / pathology*
  • PTEN Phosphohydrolase / genetics
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • CD24 Antigen
  • Integrin beta1
  • Receptor, Notch1
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • PTEN Phosphohydrolase