Cyclin-dependent kinase 6 inhibits proliferation of human mammary epithelial cells

Joseph J Lucas1, Joanne Domenico, Erwin W Gelfand

  • 1Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA. lucasj@njc.org

Insights

Loss of cdk6 protein, which normally restrains cell growth, is observed in breast tumors. Restoring cdk6 levels in cancer cells reduced their proliferation, suggesting cdk6

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Defects in G(1)-phase cyclin-dependent kinases (cdks) are common in cancer.
  • Current models suggest cdks promote cell cycle progression by inactivating growth-suppressing proteins like Rb.
  • However, cdks also contribute to the formation of growth-suppressing Rb complexes.

Purpose of the Study:

  • To investigate the role of cdk6 in breast epithelial cell proliferation and breast tumor development.
  • To determine if cdk6 functions as a growth suppressor in human mammary epithelial cells.

Main Methods:

  • Quantification of cdk6 protein and activity in normal and breast tumor-derived cell lines.
  • Immunohistochemical analysis of cdk6 expression in vivo.
  • Restoration of cdk6 levels via DNA transfection in tumor cell lines.
  • Assessment of cell proliferation rates and Rb family protein/E2F4 nuclear accumulation.

Main Results:

  • Normal human mammary epithelial cells exhibit high cdk6 levels, while breast tumor cell lines show significantly reduced or absent cdk6.
  • Restoring cdk6 in tumor cells decreased their growth rate.
  • Loss of restored cdk6 expression led to a return to faster proliferation.
  • Restored cdk6 increased nuclear accumulation of p130 and E2F4.

Conclusions:

  • Cdk6 acts as a restraint on breast epithelial cell proliferation, contrary to some models of cdk function.
  • Down-regulation or loss of cdk6 may contribute to the development of breast tumors.

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