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Haploinsufficiency of Atp2a2, Encoding the Sarco(endo)plasmic Reticulum Ca²⁺-ATPase Isoform 2 Ca²⁺ Pump, Predisposes Mice to Squamous Cell Tumors via a Novel Mode of Cancer Susceptibility

Departments of ¹ Molecular Genetics, Biochemistry and Microbiology, ² Pathology and Laboratory Medicine, and ³ Environmental Health, University of Cincinnati College of Medicine and ⁴ Division of Pediatric Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Requests for reprints: Gary E. Shull, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524. Phone: 513-588-0056; E-mail: gary.shull{at}uc.edu.

A null mutation in one copy of the Atp2a2 or ATP2A2 gene, encoding sarco(endo)plasmic reticulum Ca²⁺-ATPase isoform 2 (SERCA2), leads to squamous cell tumors in mice and to Darier disease in humans, a skin disorder that also involves keratinocytes. Here, we examined the time course and genetic mechanisms of tumor development in the mutant animals. Atp2a2^+/– mice overexpressed keratins associated with keratinocyte hyperactivation in normal forestomachs as early as 2 months of age. By the age of 5 to 7 months, 22% of mutants had developed papillomas of the forestomach, and 89% of mutants older than 14 months had developed squamous cell papillomas and/or carcinomas, with a preponderance of the latter. Tumors occurred in regions that had keratinized epithelium and were subjected to repeated mechanical irritation. The genetic mechanism of tumorigenesis did not involve loss of heterozygosity, as tumor cells analyzed by laser capture microdissection contained the wild-type Atp2a2 allele. Furthermore, immunoblot and immunohistochemical analysis showed that tumor keratinocytes expressed the SERCA2 protein. Mutations were not observed in the ras proto-oncogenes; however, expression of wild-type ras was up-regulated, with particularly high levels of K-ras. Loss of the p53 tumor suppressor gene occurred in a single massive tumor, whereas other tumors had increased levels of p53 protein but no mutations in the p53 gene. These findings show that SERCA2 haploinsufficiency predisposes mice to tumor development via a novel mode of cancer susceptibility involving a global change in the tumorigenic potential of keratinized epithelium in Atp2a2^+/– mice.

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