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.