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Proliferation and Cdk4 expression in microsatellite unstable colon cancers with TGFBR2 mutations

William M Grady1, Joseph E Willis, Patty Trobridge

  • 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. wgrady@fhcrc.org

International Journal of Cancer
|August 19, 2005
PubMed

Insights

Microsatellite instability (MSI) colon cancers with mutations in the TGF-beta receptor (TGFBR2) show increased cell proliferation and cdk4 expression. Restoring TGFBR2 function reduced proliferation and cdk4 activity, indicating TGFBR2 inactivation drives colon cancer growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Approximately 15% of human colon cancers exhibit microsatellite instability (MSI), often involving mutations in the polyadenine tract (BAT-RII) of the type II transforming growth factor beta (TGF-beta) receptor (TGFBR2).
  • Mutations in BAT-RII confer resistance to TGF-beta, a signaling molecule known to inhibit cell proliferation and induce apoptosis in epithelial cells.
  • The in vitro effects of TGF-beta signaling on cell cycle regulators are context-dependent, necessitating in vivo investigation into its role in primary colon cancer pathogenesis.

Purpose of the Study:

  • To investigate the pathogenetically relevant effects of TGFBR2 inactivation in primary MSI colon cancers with mutant BAT-RII.
  • To determine if TGFBR2 inactivation directly contributes to increased proliferation and altered cell cycle gene expression in colon cancer.

Main Methods:

  • Comparative analysis of proliferation and cell cycle-related gene expression (cdk4, cyclin D1, p27(kip1)) in colon cancers with mutant versus wild-type BAT-RII.
  • Functional rescue experiments involving the reconstitution of TGFBR2 in an MSI colon cancer cell line harboring BAT-RII mutations.
  • Assessment of proliferation, cdk4 expression, and cdk4 kinase activity following TGFBR2 reconstitution.

Main Results:

  • Colon cancers with mutant BAT-RII demonstrated significantly increased proliferation compared to those with wild-type BAT-RII.
  • Increased expression of cdk4 was observed in mutant BAT-RII colon cancers, while cyclin D1 and p27(kip1) levels did not show significant alterations.
  • Reconstitution of TGFBR2 in MSI colon cancer cells led to a reduction in cell proliferation and decreased cdk4 expression and kinase activity.

Conclusions:

  • TGFBR2 mutations in primary colon cancers are likely responsible for increased tumor cell proliferation and elevated cdk4 expression.
  • Deregulation of cdk4 represents a pathogenic consequence of TGFBR2 inactivation in vivo during colon cancer development.
  • Targeting TGF-beta signaling or its downstream effectors like cdk4 may offer therapeutic strategies for MSI colon cancers.

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