Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 Ca2+ pump

Mutations in the human ATP2A2 gene, encoding sarco(endo)plasmic reticulum C a2+-ATPase isoform 2 (SERCA2), cause Darier disease, an autosomal dominant skin disease characterized by multiple keratotic papules in the seborrheic regions of the body. Mice with a single functional Atp2a2 allele (the mouse homolog of ATP2A2) were shown previously to have reduced levels of SERCA2 in heart and mildly impaired cardiac contractility and relaxation, Here we show that aged heterozygous mutant (Atp2a2(+/-)) mice develop squamous cell tumors of the forestomach, esophagus, oral mucosa, tongue, and skin, Squam ous cell tumors occurred in 13/14 Atp2a2(+/-) mice but were not observed in age- and sex-matched wild-type controls. Hyperkeratinized squamous cell pa pillomas and carcinomas of the upper digestive tract were the most frequent finding among Atp2a2(+/-) mice, and many animals had multiple tumors. West ern blot analyses showed that SERCA2 protein levels were reduced in skin an d other affected tissues of heterozygous mice. The development of squamous cell tumors in aged Atp2a2(+/-) mice indicates that SERCA2 haploinsufficien cy predisposes murine keratinocytes to neoplasia, These findings provide th e first direct demonstration that a perturbation of Ca2+ homeostasis or sig naling can serve as a primary initiating event in cancer.