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(American Journal of Pathology. 2004;164:1031-1038.)
© 2004 American Society for Investigative Pathology

The Role of the Cyclin D1-Dependent Kinases in ErbB2-Mediated Breast Cancer

Chuanwei Yang^*, Viviana Ionescu-Tiba^*, Karen Burns, Michelle Gadd, Lawrence Zukerberg, David N. Louis, Dennis Sgroi and Emmett V. Schmidt^*¶

From the Massachusetts General Hospital (MGH) Cancer Research Center,^*the Department of Surgical Oncology,and the Pediatric Service,^¶Massachusetts General Hospital; Boston, Massachusetts; the Molecular Pathology Unit,Massachusetts General Hospital–East, Charlestown, Massachusetts; and Anatomical Pathology,The Ottawa Hospital–General Campus, Ottawa, Ontario, Canada

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.

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