Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis

Cancer Cell. 2006 Jan;9(1):13-22. doi: 10.1016/j.ccr.2005.12.019.


Cyclin D1 is a multifunctional protein that activates CDK4 and CDK6, titrates Cip/Kip CDK inhibitors to increase CDK2 activity, and modulates the function of certain transcription factors. To specifically test the importance of cyclin D1-associated kinase activity, we generated "knockin" mice expressing mutant cyclin D1 deficient in activating CDK4/6. The development of several cyclin D1-dependent compartments, including mammary glands, proceeds relatively normally in these animals, demonstrating that cyclin D1-associated kinase activity is largely dispensable for development of these tissues. Strikingly, knockin mice were resistant to breast cancers initiated by ErbB-2. These results demonstrate a differential requirement for cyclin D1-CDK4/6 kinase activity in development versus tumorigenesis and strongly support cyclin D1-dependent kinase activity as a specific therapeutic target in breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism*
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / metabolism*
  • Enzyme Activation
  • Female
  • Genes, erbB-2
  • Mammary Glands, Animal / enzymology
  • Mammary Glands, Animal / growth & development*
  • Mammary Neoplasms, Experimental / metabolism*
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Protein Binding
  • Retina / enzymology
  • Retina / growth & development


  • Cyclin D1
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6