Vulval squamous cell carcinoma arising in localized Darier’s disease

Vázquez, Julio; Morales, Cristina; González, Luis O.; Lamelas, Marı́a L.; Ribas, Andrés

doi:10.1016/s0301-2115(01)00591-7

Cited by 20 publications

(9 citation statements)

References 8 publications

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“…SERCA2 haploinsufficiency, as the mechanism of tumorigenesis in Atp2a2 +/À mice, is consistent with the observation that SERCA2 haploinsufficiency is responsible for Darier disease in ATP2A2 +/À humans (8). Although there have been only occasional reports of squamous cell carcinomas in Darier disease patients (34)(35)(36), the same cell type is affected in the Atp2a2 +/À mice, suggesting that the underlying cellular perturbations emanating from reduced SERCA2 expression are similar. The basis for the species difference in tumor susceptibility is uncertain but not surprising given the major differences in overall cancer susceptibility between humans and mice, which may involve factors, such as telomerase activity and telomere lengths (37).…”

Section: Discussionsupporting

confidence: 84%

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

Prasad¹,

Boivin²,

Miller

et al. 2005

Cancer Research

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A null mutation in one copy of the Atp2a2 or ATP2A2 gene, encoding sarco(endo)plasmic reticulum Ca 2+ -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+/À 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 +/À mice. (Cancer Res 2005; 65(19): 8655-61)

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Section: Discussionsupporting

confidence: 84%

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

Prasad¹,

Boivin²,

Miller

et al. 2005

Cancer Research

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“…Immunostaining for Ki67 (a proliferation marker) and cell cycle analysis by bromodeoxyuridine incorporation revealed enhanced proliferation in lesional keratinocytes. Analogous to DD and its murine model [23][24][25][26], the canine lesional tissues also correlated with hyperplastic histology [58].…”

Section: Store-operated Calcium Entrymentioning

confidence: 95%

“…Cellular transformations and tumorigenesis associated with DD have been much debated. There are a number of isolated reports suggesting the co-existence of DD and carcinogenesis [23][24][25], but whether DD is a cause or effect of any associated carcinogenesis still remains to be determined. Interestingly, a murine model of DD, heterozygous (+/-) for SERCA2, overexpresses the H-ras oncogene and does develop papilloma and squamous cell carcinoma at a later stage, but does not exhibit a DD-like phenotype [26,27].…”

Section: Genotype To Phenotype Perspectivementioning

confidence: 99%

Darier’s disease: a calcium-signaling perspective

Pani

Singh

2007

Cell. Mol. Life Sci.

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Ca 2+ influx evoked across the plasma membrane upon internal store depletion is essential for a myriad of cellular functions including gene expression, cell proliferation, differentiation and even apoptosis. Darier's disease (DD), an autosomal dominant inherited disorder of the skin, arising due to mutations in the isoform 2 of the sarco (endo) plasmic reticulum Ca 2+ ATPase (SERCA2), exemplifies an anomaly of Ca 2+ signaling disturbances. Owing to loss of function mutations in SERCA2, keratinocytes in DD patients have a reduced pool of endoplasmic reticulum (ER) Ca 2+ . Importantly, the status of ER Ca 2+ is critical for the activation of a class of plasma membrane Ca 2+ channels referred to as store operated Ca 2+ channels (SOCs). The widely expressed transient receptor potential (TRP) family of channels is proposed to be SOCs. In this review we discuss DD from the viewpoint of Ca 2+ signaling and present a potential role for TRPC1 in the disease pathogenesis.

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“…In mice, SERCA2 haploinsufficiency does not cause Darier disease but does lead to squamous cell tumors of keratinized epithelial cells (17,18), the same cell type affected in Darier disease. In humans, a low incidence of squamous cell tumors has been reported in both Darier disease (19) and HHD (20,21), but it is unclear whether this is a chance association or is caused by the reduction in Ca 2ϩ pump levels and activity. In the current study, we developed a gene-targeted mouse model for SPCA1 and analyzed the phenotype resulting from heterozygous and homozygous null mutations.…”

mentioning

confidence: 99%

Loss of the Atp2c1 Secretory Pathway Ca2+-ATPase (SPCA1) in Mice Causes Golgi Stress, Apoptosis, and Midgestational Death in Homozygous Embryos and Squamous Cell Tumors in Adult Heterozygotes

Okunade

Miller

Azhar

et al. 2007

Journal of Biological Chemistry

110

124

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embryos had an open rostral neural tube, but hematopoiesis and cardiovascular development were ostensibly normal. Golgi membranes of Spca1 ؊/؊ embryos were dilated, had fewer stacked leaflets, and were expanded in amount, consistent with increased Golgi biogenesis. The number of Golgi-associated vesicles was also increased, and rough endoplasmic reticulum had fewer ribosomes. Coated pits, junctional complexes, desmosomes, and basement membranes appeared normal in mutant embryos, indicating that processing and trafficking of proteins in the secretory pathway was not massively impaired. However, apoptosis was increased, possibly the result of secretory pathway stress, and a large increase in cytoplasmic lipid was observed in mutant embryos, consistent with impaired handling of lipid by the Golgi. Adult heterozygous mice appeared normal and exhibited no evidence of Hailey-Hailey disease; however, aged heterozygotes had an increased incidence of squamous cell tumors of keratinized epithelial cells of the skin and esophagus. These data show that loss of the Golgi Ca 2؉ pump causes Golgi stress, expansion of the Golgi, increased apoptosis, and embryonic lethality and demonstrates that SPCA1 haploinsufficiency causes a genetic predisposition to cancer. and Mn 2ϩ (10). Loss of PMR1 affects outer chain glycosylation, proteolytic processing, and trafficking of proteins in the secretory pathway (9). In mammals, SPCA1 is expressed in all tissues (1), whereas SPCA2 is expressed in only a limited set of tissues (3). Like PMR1, both SPCA1 and SPCA2 are localized to the Golgi and transport Ca 2ϩ and Mn 2ϩ (3, 11). There is evidence that the cell biological functions of SPCA1 are also similar to those of PMR1 (12).Loss of one copy of the human ATP2C1 gene, encoding SPCA1, causes Hailey-Hailey disease (HHD), an autosomal dominant skin disorder (13,14). SPCA1 protein levels in HHD keratinocytes are reduced to about half of normal levels, and Golgi Ca 2ϩ handling is impaired (15). HHD is similar to Darier disease, which is caused by null mutations in one copy of the human ATP2A2 gene, encoding SERCA2 (16). Both diseases are characterized by acantholysis (a disruption of cell-cell contacts) in the suprabasal layers of the skin. As the major ER Ca 2ϩ pump in most tissues, including keratinocytes, the function of SERCA2 is similar to that of SPCA1 in that it maintains luminal Ca 2ϩ concentrations in a major compartment of the secretory pathway. In mice, SERCA2 haploinsufficiency does not cause Darier disease but does lead to squamous cell tumors of keratinized epithelial cells (17, 18), the same cell type affected in Darier disease. In humans, a low incidence of squamous cell tumors has been reported in both Darier disease (19) and HHD (20, 21), but it is unclear whether this is a chance association or is caused by the reduction in Ca 2ϩ pump levels and activity. In the current study, we developed a gene-targeted mouse model for SPCA1 and analyzed the phenotype resulting from heterozygous and homozygous null mutations. The results sho...

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Vulval squamous cell carcinoma arising in localized Darier’s disease

Cited by 20 publications

References 8 publications

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

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

Darier’s disease: a calcium-signaling perspective

Loss of the Atp2c1 Secretory Pathway Ca2+-ATPase (SPCA1) in Mice Causes Golgi Stress, Apoptosis, and Midgestational Death in Homozygous Embryos and Squamous Cell Tumors in Adult Heterozygotes

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