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

L. Strizzi, C. Bianco, M. Hirota, K. Watanabe, M. Mancino, S. Hamada, A. Raafat, S. Lawson, A. D. Ebert, A. D'Antonio, S. Losito, N. Normanno, D. S. Salomon*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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-3β, and dephosphorylated (DP)-β-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 β-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-3β and increased nuclear localization of β-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-3β and dephosphorylated (DP)-β-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 β-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-3β, DP-β-catenin, and increased nuclear localization of β-catenin in human and MMTV-CR-1 mice leiomyosarcomas.

Original languageEnglish (US)
Pages (from-to)36-44
Number of pages9
JournalJournal of Pathology
Volume211
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • Cripto-1
  • Sarcoma
  • Transgenic mice
  • Uterus

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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