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Cyclin D1 overexpression combined with N-nitrosomethylbenzylamine increases dysplasia and cellular proliferation in murine esophageal squamous epithelium

Oncogene volume 18, pages 59–66 (1999)Cite this article

Abstract

We previosuly described the oral-esophageal tissue-specific expression of cyclin D1 with the Epstein – Barr virus ED-L2 promoter in transgenic mice, and resulting dysplasia. Given the evidence for an interplay between environmental and genetic factors in esophageal squamous carcinogenesis, the aim of this study was to determine the potential cooperation of the nitrosamine compound N-nitrosomethylbenzylamine (NMBA), an esophageal specific carcinogen, in the cyclin D1 transgenic mice. NMBA was first demonstrated to induce dysplasia in two strains of inbred mice, C57BL/6 and FVB/N. Subcutaneous NMBA was then administrated to wild type and transgenic mice beginning at 4 weeks of age. Mice were monitered for the duration of the study for general appearance, activity and weight, and were euthanized at 12 and 15 months. Histopathologic analysis revealed increased severity of dysplasia in cyclin D1 mice treated with NMBA compared with treated age-matched wild-type mice and untreated mice. There was also increased proliferating cell nuclear antigen (PCNA) expression in the esophagi of NMBA treated cyclin D1 mice. Taken together, these findings suggest that a genetic alteration, specifically cyclin D1 overexpression and a chemical carinogen, NMBA, may cooperate to increase the severity of esophageal squamous dysplasia, a prominent precursor to carcinoma.

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Acknowledgements

This work was supported by the ADHF/AGA Funderberg Awards (AR), an ACS Jr Faculty Research Award (AR), NIH DK53377 (AR), NIH P01 DE12467-01A1 (AR, RK), a Glaxo Wellcome Institute for Digestive Health Basic Research Award (TJ), an NIDDK K08 Award (TJ) and a Center for the Study of Inflammatory Bowel Disease Award from NIH 5P30DK 43357-08 (TJ). A. Mueller was supported by the Deutsche Forschungsgemeinschaft (DFG #1304-1-1). R. Odze was supported by the Stanley L. Robbins Research Fund from the Department of Pathology at Brigham and Women's Hospital.

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Author notes

  1. Anil K Rustgi

    Present address: Gastroenterology Division, 6CRB, University of Pennsylvania, 415 Curie Blvd, Philadelphia, PA, 19104, USA

Authors and Affiliations

  1. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School Boston, Massachusetts, USA

    Timothy D Jenkins, Annegret Mueller & Anil K Rustgi

  2. Hematology-Oncology Unit, Massachusetts General Hospital, Harvard Medical School Boston, Massachusetts, USA

    Anil K Rustgi

  3. Department of Pathology, Massachusetts General Hospital, Harvard Medical School Boston, Massachusetts, USA

    Lawrence R Zukerberg

  4. Department of Pathology, Brigham and Women's Hosptial, Harvard Medical School, Boston, Massachusetts, USA

    Robert Odze & Aliakbar Shahsafaei

  5. Forsyth Dental Center and Harvard School of Dental Medicine, Boston, Massachusetts, USA

    Ralph Kent

  6. Department of Preventive Medicine, Laboratory of Cancer Chemoprevention and Etiology, and Arthur James Cancer Hospital and Research Institute, The Ohio State University, Ohio, USA

    Gary D Stoner

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Jenkins, T., Mueller, A., Odze, R. et al. Cyclin D1 overexpression combined with N-nitrosomethylbenzylamine increases dysplasia and cellular proliferation in murine esophageal squamous epithelium. Oncogene 18, 59–66 (1999). https://doi.org/10.1038/sj.onc.1202296

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