Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis.
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.
Landis
Mark W
MW
Molecular Oncology Research Institute and Department of Radiation Oncology, Tufts-New England Medical Center, 750 Washington Street #5609, Boston, Massachusetts 02111, USA.
Pawlyk
Basil S
BS
Li
Tiansen
T
Sicinski
Piotr
P
Hinds
Philip W
PW
D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D018734:Genes, erbB-2; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000254:growth & development*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D011485:Protein Binding; D012160:Retina / Q000201:enzymology / Q000254:growth & development
D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6