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Separase, a protease encoded by the ESPL1 gene, cleaves the chromosomal cohesin during mitosis. Separase protein and transcripts are overexpressed in a wide range of human cancers. To investigate the physiological consequence of Separase overexpression in animals, we have generated a transgenic MMTV-Espl1 mouse model that overexpresses Separase protein in the mammary glands. MMTV-Espl1 mice in a C57BL/6 genetic background develop aggressive, highly aneuploid and estrogen receptor alpha-positive (ERα+) mammary adenocarcinomas with an 80% penetrance. The mammary tumors caused by overexpression of Separase, alone or combined with p53 heterozygosity, in mammary epithelium mimic several aspects of the most aggressive forms of human breast cancer, including high levels of genetic instability, cell cycle defects, poor differentiation, distant metastasis and metaplasia. Histopathologically, MMTV-Espl1 tumors are highly heterogeneous showing features of both luminal as well as basal subtypes of breast cancers, with aggressive disease phenotype. In addition to aneuploidy, Separase overexpression results in chromosomal instability (CIN) including premature chromatid separation (PCS), lagging chromosomes, anaphase bridges, micronuclei, centrosome amplification, multinucleated cells, gradual accumulation of DNA damage and progressive loss of tumor suppressors p53 and cadherin gene loci. These results suggest that Separase-overexpressing mammary cells are not only susceptible to chromosomal missegregation-induced aneuploidy but also other genetic instabilities including DNA damage and loss of key tumor suppressor gene loci, which in combination can initiate tumorigenesis and disease progression.
Pubmed ID: 24276237 RIS Download
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The web site includes genomic data for humans and mice, including transcript sequence, gene expression patterns, single-nucleotide polymorphisms, clone resources, and cytogenetic information. Descriptions of the methods and reagents used in deriving the CGAP datasets are also provided. An extensive suite of informatics tools facilitates queries and analysis of the CGAP data by the community. One of the newest features of the CGAP web site is an electronic version of the Mitelman Database of Chromosome Aberrations in Cancer. The data in the Mitelman Database is manually culled from the literature and subsequently organized into three distinct sub-databases, as follows: -The sub-database of cases contains the data that relates chromosomal aberrations to specific tumor characteristics in individual patient cases. It can be searched using either the Cases Quick Searcher or the Cases Full Searcher. -The sub-database of molecular biology and clinical associations contains no data from individual patient cases. Instead, the data is pulled from studies with distinct information about: -Molecular biology associations that relate chromosomal aberrations and tumor histologies to genomic sequence data, typically genes rearranged as a consequence of structural chromosome changes. -Clinical associations that relate chromosomal aberrations and/or gene rearrangements and tumor histologies to clinical variables, such as prognosis, tumor grade, and patient characteristics. It can be searched using the Molecular Biology and Clinical (MBC) Associations Searcher -The reference sub-database contains all the references culled from the literature i.e., the sum of the references from the cases and the molecular biology and clinical associations. It can be searched using the Reference Searcher. CGAP has developed six web search tools to help you analyze the information within the Mitelman Database: -The Cases Quick Searcher allows you to query the individual patient cases using the four major fields: aberration, breakpoint, morphology, and topography. -The Cases Full Searcher permits a more detailed search of the same individual patient cases as above, by including more cytogenetic field choices and adding search fields for patient characteristics and references. -The Molecular Biology Associations Searcher does not search any of the individual patient cases. It searches studies pertaining to gene rearrangements as a consequence of cytogenetic aberrations. -The Clinical Associations Searcher does not search any of the individual patient cases. It searches studies pertaining to clinical associations of cytogenetic aberrations and/or gene rearrangements. -The Recurrent Chromosome Aberrations Searcher provides a way to search for structural and numerical abnormalities that are recurrent, i.e., present in two or more cases with the same morphology and topography. -The Reference Searcher queries only the references themselves, i.e., the references from the individual cases and the molecular biology and clinical associations. Sponsors: This database is sponsored by the University of Lund, Sweden and have support from the Swedish Cancer Society and the Swedish Children''s Cancer Foundation
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View all literature mentionsA contract research organization providing drug development and animal testing services. Under the name Covance Research Products Inc., based in Denver, Pennsylvania, the company also deals in the import, breeding and sale of laboratory animals. It breeds dogs, rabbits, guinea pigs, non-human primates, and pigs, and runs the largest non-human primate laboratory in Germany. (Wikipedia)
View all literature mentionsCommercial organization that supplies antibodies, proteins, ELISA kits, serum, and plasma to the research community.
View all literature mentionsAllele Detail: Transgenic This is a legacy resource.
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