The Mouse Tumor Biology database

Krupke, Debra M.; Begley, Dale A.; Sundberg, John P.; Bult, Carol J.; Eppig, Janan T.

doi:10.1038/nrc2390

Cited by 67 publications

(59 citation statements)

References 28 publications

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“…This idea can be examined by generating mito-miceND6 M carrying G13997A mtDNA but in a nuclear genetic background derived from another wild-type mouse strain that preferentially develops tumors other than B lymphoma. It has been proposed that nuclear genetic variations among wild-type mouse strains affect the tumor formation spectrum (27)(28)(29)(30), particularly when genetic manipulations are performed to induce tumor development (29,30). Thus, the generation of new mitomiceND6 M would be effective for examining the issue of whether G13997A mtDNA enhances the development of different tumors in different nuclear genetic backgrounds or whether it specifically enhances B-lymphoma development irrespective of whether the nuclear genetic background is derived from B6 or not.…”

Section: Discussionmentioning

confidence: 99%

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Hashizume

Shimizu

Yokota

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mitomice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis-but not aging-in this model. reactive oxygen species generating mutation | Warburg effect | chromosome aberration | lactic acidosis | hyperglycemia P athogenic mitochondrial DNA (mtDNA) mutations that induce significant mitochondrial respiration defects are responsible for mitochondrial diseases (1, 2) and could also be involved in aging and age-associated disorders, including tumor development (1-5). On the other hand, mitochondrial respiration defects caused by nuclear DNA mutations and the resultant enhanced glycolysis under normoxic conditions, i.e., the Warburg effect, are proposed to be involved in tumor development (6-9). Because pathogenic mtDNA mutations also induce mitochondrial respiration defects and up-regulation of aerobic glycolysis, accumulation of these mtDNA mutations with age could also be responsible for tumor development. In addition, it is possible that mtDNA mutations regulate tumor development as a consequence of overproduction of reactive oxygen species (ROS) and the resultant induction of genetic instability (1, 2, 10). In fact, somatic mtDNA mutations are preferentially accumulated in human tumor cells (11-13), and a germline mtDNA mutation (A8344G) in the tRNA Lys gene has been found in lipomas (benign adipose tissue tumors) (14). However, there is as yet no direct evidence for the contribution of mtDNA mutations to aging and tumor development, because of the difficulty of excluding the possible contribution of nuclear DNA mutations, including copy-number variants (CNVs), to these processes (2, 15).Our previous study (16) resolved this issue by using complete mtDNA exchange technology between mouse normal and tumor cells, and we showed that exogenously introduced mtDNA does not affect tumorigenicity. In contrast, our recent study (17) performed exchange of mtDNA between poorly and highly metastatic mouse tumor cells, providing convincing evidence that the somatic mtDNA mutation G13997A in the ND6 gene, which encodes one of the subunits of respiration complex I (NADH dehydrogenase), re...

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Section: Discussionmentioning

confidence: 99%

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Hashizume

Shimizu

Yokota

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Circle Manhattan Plot was generated using CIRCOS software. Regions of mouse genome showing significant gain or loss in aCGH analysis were visualized in a chromosome-wise manner using the cancer QTL viewer of Mouse Tumor Biology Database (28).…”

Section: Array Cghmentioning

confidence: 99%

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

Treekitkarnmongkol

Katayama

Kai

et al. 2016

CARCIN

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Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.

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“…The Pathbase database includes macroscopic images and histopathology photomicrographs that can be retrieved by searching for specific lesions or by class of lesion, genetic locus, or other parameters. 26,130,206,211,252 …”

Section: Genetic Background: Expected Pathology Phenotypes and Causesmentioning

confidence: 99%

Pathobiology of Aging Mice and GEM

2012

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The use of induced and spontaneous mutant mice and genetically engineered mice (and combinations thereof) to study cancers and other aging phenotypes to advance improved functional human life spans will involve studies of aging mice. Genetic background contributes to pathology phenotypes and to causes of death as well as to longevity. Increased recognition of expected phenotypes, experimental variables that influence phenotypes and research outcomes, and experimental design options and rationales can maximize the utility of genetically engineered mice (GEM) models to translational research on aging. This review aims to provide resources to enhance the design and practice of chronic and longevity studies involving GEM. C57BL6, 129, and FVB/N strains are emphasized because of their widespread use in the generation of knockout, transgenic, and conditional mutant GEM. Resources are included also for pathology of other inbred strain families, including A, AKR, BALB/c, C3H, C57L, C58, CBA, DBA, GR, NOD.scid, SAMP, and SJL/J, and non-inbred mice, including 4WC, AB6F1, Ames dwarf, B6, 129, B6C3F1, BALB/c,129, Het3, nude, SENCAR, and several Swiss stocks. Experimental strategies for long-term cross-sectional and longitudinal studies to assess causes of or contributors to death, disease burden, spectrum of pathology phenotypes, longevity, and functional healthy life spans (health spans) are compared and discussed.

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The Mouse Tumor Biology database

Cited by 67 publications

References 28 publications

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

Pathobiology of Aging Mice and GEM

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