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Cancer development induced by graded expression of Snail in mice

Pedro Antonio Pérez-Mancera1, María Pérez-Caro, Inés González-Herrero

  • 1Laboratorio 13, Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC/Universidad de Salamanca, Campus Unamuno, Spain.

Human Molecular Genetics
|October 7, 2005
PubMed

Insights

This study reveals that elevated Snail levels, a key epithelial-mesenchymal transition (EMT) regulator, are crucial for cancer development in mammals. DNA damage influences Snail expression, impacting cell fate during genotoxic stress responses.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Developmental Biology

Background:

  • The zinc-finger transcription factor Snail is implicated in epithelial-mesenchymal transitions (EMTs) and cancer progression.
  • Previous studies in knockout mice and cancer patients suggest Snail's role, but a direct causal link to cancer pathogenesis is lacking.

Purpose of the Study:

  • To investigate the direct role of Snail in cancer development and its regulation by DNA damage.
  • To establish a genetic link between Snail, EMT, and mammalian cancer pathogenesis.

Main Methods:

  • Utilized hypomorphic tetracycline-repressible Snail transgenes in mice to modulate Snail expression levels.
  • Generated CombitTA-Snail murine embryonic fibroblasts (MEFs) for in vitro and in vivo tumor formation studies.
  • Assessed Snail's role in radioprotection and p53 regulation following DNA damage.

Main Results:

  • Mice with moderately increased Snail expression developed epithelial and mesenchymal tumors (leukaemias), with the malignant phenotype being irreversible upon Snail suppression.
  • CombitTA-Snail-MEFs induced tumor formation in nude mice, despite similar migratory abilities to control MEFs.
  • Snail expression was repressed following DNA damage in a p53-independent manner, suggesting a role in the genotoxic stress response.

Conclusions:

  • Provides genetic evidence that Snail plays essential roles in mammalian cancer development.
  • Connects DNA damage to the requirement of a critical level of an EMT regulator, influencing cell fate.
  • Suggests Snail's function in cancer pathogenesis is linked to its role in the genotoxic stress response.

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