Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells.
A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies. Here we test this idea by transiently blocking cytokinesis in p53-null (p53-/-) mouse mammary epithelial cells (MMECs), enabling the isolation of diploid and tetraploid cultures. The tetraploid cells had an increase in the frequency of whole-chromosome mis-segregation and chromosomal rearrangements. Only the tetraploid cells were transformed in vitro after exposure to a carcinogen. Furthermore, in the absence of carcinogen, only the tetraploid cells gave rise to malignant mammary epithelial cancers when transplanted subcutaneously into nude mice. These tumours all contained numerous non-reciprocal translocations and an 8-30-fold amplification of a chromosomal region containing a cluster of matrix metalloproteinase (MMP) genes. MMP overexpression is linked to mammary tumours in humans and animal models. Thus, tetraploidy enhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs.
Fujiwara
Takeshi
T
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bandi
Madhavi
M
Nitta
Masayuki
M
Ivanova
Elena V
EV
Bronson
Roderick T
RT
Pellman
David
D
D000818:Animals; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D017690:Cell Transplantation; D002869:Chromosome Aberrations; D048749:Cytokinesis / Q000235:genetics* / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009208:Myoepithelioma / Q000235:genetics / Q000473:pathology; D011123:Polyploidy; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D016159:Tumor Suppressor Protein p53; D020782:Matrix Metalloproteinases