Development of leiomyosarcoma of the uterus in MMTV-CR-1 transgenic mice

J Pathol. 2007 Jan;211(1):36-44. doi: 10.1002/path.2083.


Overexpression of Cripto-1 (CR-1) in FVB/N mice using the MMTV-LTR promoter results in increased mammary tumourigenesis in these female transgenic mice (MMTV-CR-1). Here, we characterize uterine tumours that developed in 15/76 (19.7%) of MMTV-CR-1 female nulliparous or multiparous mice during 24 months of observation compared with 0/33 (0%) of FVB/N normal control mice observed during the same time period (p < 0.01). The uterine tumours collected from the MMTV-CR-1 mice were classified as leiomyosarcomas and found to express the CR-1 transgene by polymerase chain reaction analysis and immunohistochemistry. Detection by western blot analysis showed higher levels of phosphorylated (P) forms of c-src, Akt, GSK-3beta, and dephosphorylated (DP)-beta-catenin in lysates from MMTV-CR-1 uterine leiomyosarcomas in comparison with lysates from normal control FVB/N uteri. Immunostaining showed increased nuclear localization of beta-catenin in the MMTV-CR-1 uterine leiomyosarcomas. Increased immunostaining for CR-1 was detected in 9/13 (69.2%) cases of human leiomyosarcoma compared with staining in 3/15 (20%) human leiomyoma sections. Stronger immunostaining for P-src, P-Akt, P-GSK-3beta and increased nuclear localization of beta-catenin was also seen in human leiomyosarcomas in comparison with leiomyomas. Normal human uterine smooth muscle (UtSM) cells treated with exogenous soluble rhCR-1 showed increased levels of P-src, P-Akt, P-GSK-3beta and dephosphorylated (DP)-beta-catenin and increased proliferation (p < 0.05) and migration (p < 0.01) in comparison with untreated control UtSM cells. Inhibitors against c-src, Akt or beta-catenin, individually or in combination, significantly reduced CR-1-induced migration. These results suggest a role for CR-1 during uterine tumourigenesis either directly by activating c-src and Akt and/or via cross-talk with the canonical Wnt signalling pathway, as suggested by the increased expression of P-GSK-3beta, DP-beta-catenin, and increased nuclear localization of beta-catenin in human and MMTV-CR-1 mice leiomyosarcomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western / methods
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Epidermal Growth Factor / genetics*
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • Female
  • GPI-Linked Proteins
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry / methods
  • Intercellular Signaling Peptides and Proteins
  • Leiomyosarcoma / chemistry
  • Leiomyosarcoma / genetics
  • Leiomyosarcoma / pathology*
  • Mammary Tumor Virus, Mouse / genetics
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / pharmacology
  • Polymerase Chain Reaction / methods
  • Promoter Regions, Genetic
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Uterine Neoplasms / chemistry
  • Uterine Neoplasms / genetics
  • Uterine Neoplasms / pathology*
  • Wnt1 Protein / analysis
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism


  • GPI-Linked Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Recombinant Proteins
  • TDGF1 protein, human
  • Wnt1 Protein
  • Epidermal Growth Factor