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A Transgenic Mouse Model with Cyclin D1 Overexpression Results in Cell Cycle, Epidermal Growth Factor Receptor, and p53 Abnormalities¹

Gastrointestinal Unit [A. M., T. D. J., H. N., T. I., A. K. R.], Hematology-Oncology Unit [A. K. R.], Massachusetts General Hospital, and Department of Pathology, Brigham and Women's Hospital [R. O., A. S.], Harvard Medical School, Boston, Massachusetts 02114

The cyclin D1 oncogene is critical in the progression of the cell cycle through the G₁ phase. It is frequently overexpressed in squamous cell carcinomas originating from the head/neck and esophagus. Yet, the functional consequences of aberrant cyclin D1 overexpression are not entirely understood apart from increased cell proliferation. To address this question, we have developed a transgenic mouse model in which the EBV ED-L2 promoter targets cyclin D1 to the stratified squamous epithelium in a tissue-specific fashion to the tongue and esophagus, thereby resulting in a dysplastic phenotype. We now demonstrate that the dysplastic phenotype is associated with increased cell proliferation based on proliferating cell nuclear antigen overexpression and abnormalities in cyclin-dependent kinase 4, epidermal growth factor receptor, and p53. In aggregate, these studies suggest that alterations in certain oncogenes and tumor suppressor genes occur early during head/neck and esophageal carcinogenesis.

¹ This work was supported by the ADHF/AGA Fiterman and Funderburg Awards (to A. K. R.), an American Cancer Society Jr. Faculty Research Award JFRA-649 (to A. K. R.), NIH Grants DK40561 and DK53377 (to A. K. R.), and Department of Energy DE-FG-2-91-ER61228 Award (to H. N. and A. K. R.). A. M. was supported by the Deutsche Forschungsgemeinschaft (1304-1-1). R. O. was supported by the Stanley L. Robbins Research Fund from the Department of Pathology at Brigham and Women's Hospital. T. J. was supported by the Glaxo Wellcome Institute for Digestive Health Award.

² To whom requests for reprints should be addressed, at Gastrointestinal and Hematology-Oncology Units, Jackson 904, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114. Phone: (617)724-3740; Fax: (617)726-3673; E-mail: rustgi@helix.mgh.harvard.edu.

Received 4/14/97. Accepted 10/15/97.

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