Overexpression of Separase induces aneuploidy and mammary tumorigenesis.
Separase is an endopeptidase that separates sister chromatids by cleaving cohesin Rad21 during the metaphase-to-anaphase transition. Conditional expression of Separase in tetracycline-inducible diploid FSK3 mouse mammary epithelial cells with both p53 WT and mutant (Ser-233-234) alleles of unknown physiological significance develops aneuploidy within 5 days of Separase induction in vitro. Overexpression of Separase induces premature separation of chromatids, lagging chromosomes, and anaphase bridges. In an in vivo mouse mammary transplant model, induction of Separase expression in the transplanted FSK3 cells for 3-4 weeks results in the formation of aneuploid tumors in the mammary gland. Xenograft studies combined with histological and cytogenetic analysis reveal that Separase-induced tumors are clonal in their genomic complements and have a mesenchymal phenotype suggestive of an epithelial-mesenchymal transition. Induction of Separase resulted in trisomies for chromosomes 8, 15, and 17; monosomy for chromosome 10; and amplification of the distal region of chromosomes 8 and 11. Separase protein is found to be significantly overexpressed in human breast tumors compared with matched normal tissue. These results collectively suggest that Separase is an oncogene, whose overexpression alone in mammary epithelial cells is sufficient to induce aneuploidy and tumorigenesis in a p53 mutant background.
Zhang
Nenggang
N
Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, Houston, TX 77030, USA.
Ge
Gouquing
G
Meyer
Rene
R
Sethi
Sumita
S
Basu
Dipanjan
D
Pradhan
Subhashree
S
Zhao
Yi-Jue
YJ
Li
Xiao-Nan
XN
Cai
Wei-Wen
WW
El-Naggar
Adel K
AK
Baladandayuthapani
Veerabhadran
V
Kittrell
Frances S
FS
Rao
Pulivarthi H
PH
Medina
Daniel
D
Pati
Debananda
D
D000705:Anaphase; D000782:Aneuploidy; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002842:Chromatids / Q000201:enzymology; D043171:Chromosomal Instability; D010450:Endopeptidases / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology*; D008677:Metaphase; D051379:Mice; D009693:Nucleic Acid Hybridization; D064247:Separase; D013752:Tetracycline
D018797:Cell Cycle Proteins; D010450:Endopeptidases; C577987:ESPL1 protein, human; D064247:Separase; D013752:Tetracycline