Overexpression and mislocalization of the chromosomal segregation protein separase in multiple human cancers.
OBJECTIVE
Separase, an endopeptidase, plays a pivotal role in chromosomal segregation by separating sister chromatids during the metaphase to anaphase transition. Using a mouse mammary tumor model we have recently shown that overexpression of Separase induces aneuploidy and tumorigenesis (Zhang et al., Proc Natl Acad Sci 2008;105:13033). In the present study, we have investigated the expression level of Separase across a wide range of human tumors.


METHODS
To examine the expression levels and localization of Separase in human tumors, we have performed immunofluorescence microscopy using human Separase antibody and tumor tissue arrays from osteosarcoma, colorectal, breast, and prostate cancers with appropriate normal controls.


RESULTS
We show that Separase is significantly overexpressed in osteosarcoma, breast, and prostate tumor specimens. There is a strong correlation of tumor status with the localization of Separase into the nucleus throughout all stages of the cell cycle. Unlike the normal control tissues, where Separase localization is exclusively cytoplasmic in nondividing cells, human tumor samples show significantly higher number of resting cells with a strong nuclear Separase staining. Additionally, overexpression of Separase transcript strongly correlates with high incidence of relapse, metastasis, and lower 5-year overall survival rate in breast and prostate cancer patients.


CONCLUSIONS
These results further strengthen our hypothesis that Separase might be an oncogene, whose overexpression induces tumorigenesis, and indicates that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human cancers.
Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Rene
R
Meyer
Viacheslav
V
Fofanov
Anilk
A
Panigrahi
Fatima
F
Merchant
Nenggang
N
Zhang
Debananda
D
Pati
D014408:Biomarkers, Tumor / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020090:Chromosome Segregation; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D016015:Logistic Models; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D064247:Separase; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D010450:Endopeptidases; C577987:ESPL1 protein, human; D064247:Separase