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Molecular and Cellular Biology, April 2002, p. 2204-2219, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2204-2219.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

ErbB2/Neu-Induced, Cyclin D1-Dependent Transformation Is Accelerated in p27-Haploinsufficient Mammary Epithelial Cells but Impaired in p27-Null Cells

Rebecca S. Muraoka,1 Anne E. G. Lenferink,2,{dagger} Brian Law,1 Elizabeth Hamilton,1 Dana M. Brantley,2 L. Renee Roebuck,2 and Carlos L. Arteaga1,2,3*

Departments of Cancer Biology,1 Medicine,2 Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 372323

Received 3 August 2001/ Returned for modification 2 October 2001/ Accepted 18 December 2001

ErbB2/Neu destabilizes the cyclin-dependent kinase (Cdk) inhibitor p27 and increases expression of cyclin D1. Therefore, we studied the roles of p27 and cyclin D1 in ErbB2-mediated mammary epithelial cell transformation. Overexpression of ErbB2 or cyclin D1 in p27+/- primary murine mammary epithelial cells resulted in increased proliferation, cyclin D1 nuclear localization, and colony formation in soft agar compared to those in p27+/+ cells. In contrast, ErbB2- or cyclin D1-overexpressing p27-/- cells displayed reduced proliferation, anchorage-independent growth, Cdk4 activity, cyclin D1 expression, and cyclin D1 nuclear localization compared to wild-type cells. A cyclin D1 mutation in its nuclear export sequence (T286A) partially rescued nuclear localization of cyclin D1 in p27-/- cells but did not increase proliferation or Cdk4 kinase activity. Overexpression of E2F1, however, increased proliferation to the same degree in p27+/+, p27+/-, and p27-/- cells. Mammary glands from MMTV (mouse mammary tumor virus)-neu/p27+/- mice exhibited alveolar hyperplasia, enhanced proliferation, decreased apoptosis, and accelerated tumor formation compared to MMTV-neu/p27+/+ glands. However, MMTV-neu/p27-/- glands showed decreased proliferation, cyclin D1 expression, and Cdk4 activity, as well as markedly prolonged tumor latency, compared to MMTV-neu/p27+/+ glands. These results suggest that p27+/- mammary epithelium may be more susceptible to oncogene-induced tumorigenesis, whereas p27-null glands, due to severely impaired cyclin D1/Cdk4 function, are more resistant to transformation.

* Corresponding author. Mailing address: Division of Oncology, Vanderbilt University School of Medicine, 777 Preston Research Bldg., Nashville, TN 37232-6307. Phone: (615) 936-3524. Fax: (615) 936-1790. E-mail: carlos.arteaga{at}mcmail.vanderbilt.edu.

{dagger} Present address: Biotechnology Research Institute, National Research Council, Montreal, Quebec, Canada.

Molecular and Cellular Biology, April 2002, p. 2204-2219, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2204-2219.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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