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Squamous cell tumors in mice heterozygous for a null allele of Atp2a2, encoding the sarco(endo)plasmic reticulum
L H Liu1, G P Boivin, V Prasad
1Departments of Molecular Genetics, Biochemistry and Microbiology and Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Abstract:
Mutations in the human ATP2A2 gene, encoding sarco(endo)plasmic reticulum Ca(2+)-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. Squamous cell tumors occurred in 13/14 Atp2a2(+/-) mice but were not observed in age- and sex-matched wild-type controls. Hyperkeratinized squamous cell papillomas and carcinomas of the upper digestive tract were the most frequent finding among Atp2a2(+/-) mice, and many animals had multiple tumors. Western blot analyses showed that SERCA2 protein levels were reduced in skin and other affected tissues of heterozygous mice. The development of squamous cell tumors in aged Atp2a2(+/-) mice indicates that SERCA2 haploinsufficiency predisposes murine keratinocytes to neoplasia. These findings provide the first direct demonstration that a perturbation of Ca(2+) homeostasis or signaling can serve as a primary initiating event in cancer.
Insights
Mutations in the ATP2A2 gene, encoding sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2), lead to Darier disease. Haploinsufficiency of SERCA2 in mice causes squamous cell tumors, indicating its role in cancer development.
Area of Science:
- Oncology
- Genetics
- Cell Biology
Background:
- Mutations in the ATP2A2 gene cause Darier disease, a skin disorder.
- Reduced SERCA2 levels in mice impact cardiac function.
- SERCA2 (sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2) is crucial for calcium homeostasis.
Purpose of the Study:
- To investigate the role of SERCA2 haploinsufficiency in cancer development.
- To determine if reduced SERCA2 levels predispose to neoplasia.
Main Methods:
- Analysis of aged heterozygous mutant (Atp2a2(+/-)) mice.
- Tumor incidence assessment in mutant versus wild-type mice.
- Western blot analysis to quantify SERCA2 protein levels in affected tissues.
Main Results:
- Aged Atp2a2(+/-) mice developed squamous cell tumors in the forestomach, esophagus, oral mucosa, tongue, and skin (13/14 mice).
- No tumors were observed in age- and sex-matched wild-type controls.
- Reduced SERCA2 protein levels were confirmed in the skin and other affected tissues of heterozygous mice.
Conclusions:
- SERCA2 haploinsufficiency predisposes murine keratinocytes to neoplasia, leading to squamous cell tumors.
- Perturbation of calcium homeostasis/signaling by SERCA2 deficiency can initiate cancer.
- This study provides the first direct evidence linking calcium signaling defects to cancer initiation.
