title: MMTV-Espl1 transgenic mice develop aneuploid, estrogen receptor alpha (ERα)-positive mammary adenocarcinomas.
abstract: 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.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatric Hematology/Oncology, Houston, TX 77030.
authors.forename: Malini
authors.initials: M
authors.lastname: Mukherjee
authors.affiliation: Texas Children's Cancer Center, Department of Pediatric Hematology/Oncology, Houston, TX 77030.
authors.forename: Gouqing
authors.initials: G
authors.lastname: Ge
authors.affiliation: Texas Children's Cancer Center, Department of Pediatric Hematology/Oncology, Houston, TX 77030.
authors.forename: Nenggang
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Molecular and Cellular Biology; Baylor College of Medicine, Houston, TX 77030.
authors.forename: David G
authors.initials: DG
authors.lastname: Edwards
authors.affiliation: Texas Children's Cancer Center, Department of Pediatric Hematology/Oncology, Houston, TX 77030.
authors.forename: Pavel
authors.initials: P
authors.lastname: Sumazin
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702.
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Sharan
authors.affiliation: Texas Children's Cancer Center, Department of Pediatric Hematology/Oncology, Houston, TX 77030.
authors.forename: Pulivarthi H
authors.initials: PH
authors.lastname: Rao
authors.affiliation: Molecular and Cellular Biology; Baylor College of Medicine, Houston, TX 77030.
authors.forename: Daniel
authors.initials: D
authors.lastname: Medina
authors.affiliation: Texas Children's Cancer Center, Department of Pediatric Hematology/Oncology, Houston, TX 77030.|Molecular and Cellular Biology; Baylor College of Medicine, Houston, TX 77030.
authors.forename: Debananda
authors.initials: D
authors.lastname: Pati
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000782:Aneuploidy; D000818:Animals; D015153:Blotting, Western; D055028:Comparative Genomic Hybridization; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064247:Separase / Q000235:genetics* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D064247:Separase