The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer

Am J Pathol. 2004 Mar;164(3):1031-8. doi: 10.1016/S0002-9440(10)63190-2.

Abstract

Intact cyclin D1 functions are essential for transformation by erbB2 in tissue culture and murine models. Because cyclin D1 may alter cell proliferation through a variety of mechanisms, we used transgenic models and human tumor samples to particularly address the role of cyclin D1-cyclin-dependent kinases in transformation by erbB2. The p16 tumor suppressor specifically blocks cyclin-dependent kinase 4 and 6 activity. Here we show that an MMTV-p16 transgene blocked tumorigenesis by erbB2, demonstrating that deregulation of the cyclin-dependent kinase partner of cyclin D1 is an essential target of erbB2. ErbB2 overexpression was a determining factor in deregulation of cyclin D1-cdk4/6 interactions because neither transgenic cyclin D1 nor loss of p16 accelerated tumorigenesis in MMTV-erbB2-transgenic mice. ErbB2 was also a deciding factor in deregulation of cyclin D1-cdk4/6 in human tumors because no loss of pRb or p16 was found in tumors overexpressing erbB2, although erbB2-negative invasive breast adenocarcinomas frequently lacked expression of p16 or pRb. We conclude that deregulation of cyclin D1-Cdk4/6 interactions is a critical target of erbB2 function in human and mouse breast tumors, and erbB2's overexpression may be sufficient to deregulate cyclin D1-cdk4/6 activity in breast cancer.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology*
  • CDC2 Protein Kinase / metabolism*
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases / metabolism
  • DNA Primers
  • Genes, erbB-2 / physiology*
  • Genes, p16 / physiology
  • Humans
  • Immunohistochemistry
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins*
  • Receptors, Virus / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • DNA Primers
  • Fam89b protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Receptors, Virus
  • Cyclin D1
  • CDC2 Protein Kinase
  • CDK4 protein, human
  • CDK6 protein, human
  • Cdk4 protein, mouse
  • Cdk6 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases