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Molecular and Cellular Biology, January 2002, p. 635-643, Vol. 22, No. 2
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.2.635-643.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Obligate Roles for p16^Ink4a and p19^Arf-p53 in the Suppression of Murine Pancreatic Neoplasia

Department of Adult Oncology, Dana-Farber Cancer Institute,¹ Departments of Pathology and Medicine,² Molecular Genetics Section, Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland,³ Brigham and Women’s Hospital,⁴ Department of Genetics, Harvard Medical School, Boston, Massachusetts⁵

Received 24 August 2001/ Returned for modification 8 October 2001/ Accepted 17 October 2001

Epithelial tumors of the pancreas exhibit a wide spectrum of histologies with varying propensities for metastasis and tissue invasion. The histogenic relationship among these tumor types is not well established; moreover, the specific role of genetic lesions in the progression of these malignancies is largely undefined. Transgenic mice with ectopic expression of transforming growth factor alpha (TGF-) in the pancreatic acinar cells develop tubular metaplasia, a potential premalignant lesion of the pancreatic ductal epithelium. To evaluate the cooperative interactions between TGF- and signature mutations in pancreatic tumor genesis and progression, TGF transgenic mice were crossed onto Ink4a/Arf and/or p53 mutant backgrounds. These compound mutant mice developed a novel pancreatic neoplasm, serous cystadenoma (SCA), presenting as large epithelial tumors bearing conspicuous gross and histological resemblances to their human counterpart. TGF animals heterozygous for both the Ink4a/Arf and the p53 mutation showed a dramatically increased incidence of SCA, indicating synergistic interaction of these alleles. Inactivation of p16^Ink4a by loss of heterozygosity, intragenic mutation, or promoter hypermethylation was a common feature in these SCAs, and correspondingly, none of the tumors expressed wild-type p16^Ink4a. All tumors sustained loss of p53 or Arf, generally in a mutually exclusive fashion. The tumor incidence data and molecular profiles establish a pathogenic role for the dual inactivation of p16^Ink4a and p19^Arf-p53 in the development of SCA in mice, demonstrating that p16^Ink4a is a murine tumor suppressor. This genetically defined model provides insights into the molecular pathogenesis of SCA and serves as a platform for dissection of cell-specific programs of epithelial tumor suppression.

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