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Molecular and Cellular Biology, September 2004, p. 7598-7611, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7598-7611.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cyclin D1 Genetic Heterozygosity Regulates Colonic Epithelial Cell Differentiation and Tumor Number in ApcMin Mice

James Hulit,1,{dagger} Chenguang Wang,2,{dagger} Zhiping Li,2 Chris Albanese,2 Mahadev Rao,2 Dolores Di Vizio,1 Salimuddin Shah,2 Stephen W. Byers,2 Radma Mahmood,1 Leonard H. Augenlicht,1 Robert Russell,2 and Richard G. Pestell2*

Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D.C.,2 The Albert Einstein Cancer Center, Einstein College of Medicine, Bronx, New York1

Received 18 December 2003/ Returned for modification 27 January 2004/ Accepted 7 June 2004

Constitutive ß-catenin/Tcf activity, the primary transforming events in colorectal carcinoma, occurs through induction of the Wnt pathway or APC gene mutations that cause familial adenomatous polyposis. Mice carrying Apc mutations in their germ line (ApcMin) develop intestinal adenomas. Here, the crossing of ApcMin with cyclin D1–/– mice reduced the intestinal tumor number in animals genetically heterozygous or nullizygous for cyclin D1. Decreased tumor number in the duodenum, intestines, and colons of ApcMin/cyclin D1+/– mice correlated with reduced cellular proliferation and increased differentiation. Cyclin D1 deficiency reduced DNA synthesis and induced differentiation of colonic epithelial cells harboring mutant APC but not wild-type APC cells in vivo. In previous studies, the complete loss of cyclin D1 through homozygous genetic deletion conveyed breast tumor resistance. The protection of mice, genetically predisposed to intestinal tumorigenesis, through cyclin D1 heterozygosity suggests that modalities that reduce cyclin D1 abundance could provide chemoprotection.

* Corresponding author. Mailing address: The Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Research Building Room E501, 3970 Reservoir Rd., N.W., Box 571468, Washington, DC 20057-1468. Phone: (202) 687-2110. Fax: (202) 687-6402. E-mail: pestell{at}georgetown.edu.

{dagger} J.H. and C.W. contributed equally to this study.

Molecular and Cellular Biology, September 2004, p. 7598-7611, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7598-7611.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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