The role of the cyclin D1-dependent kinases in ErbB2-mediated breast cancer.
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.
Massachusetts General Hospital (MGH) Cancer Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Chuanwei
C
Yang
Viviana
V
Ionescu-Tiba
Karen
K
Burns
Michelle
M
Gadd
Lawrence
L
Zukerberg
David N
DN
Louis
Dennis
D
Sgroi
Emmett V
EV
Schmidt
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology*; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D017931:DNA Primers; D018734:Genes, erbB-2 / Q000502:physiology*; D019942:Genes, p16 / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins; D011991:Receptors, Virus / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; C111417:Fam89b protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011991:Receptors, Virus; D019938:Cyclin D1; D016203:CDC2 Protein Kinase; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases