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Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells

Abstract

A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies1,2,3. 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 models4. Thus, tetraploidy enhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs.

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Figure 1: Tetraploid p53 -/- MMECs are viable, but develop numerical and structural chromosomal abnormalities after passage.
Figure 2: Transformation of tetraploid p53 -/- MMECs after carcinogen treatment.
Figure 3: Tetraploid p53 -/- MMECs spontaneously generate malignant myoepitheliomas after subcutaneous transplantation into nude mice.
Figure 4: Gross chromosomal rearrangements in tumours from tetraploid p53 -/- MMECs.

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Acknowledgements

We are grateful to S. Artandi, L. Chin, R. DePinho, C. M. Kuperwasser, M. E. McLaughlin, K. Polyak, A. Protopopov, J. Ruderman, J. Sage, P. Sicinski, T. Stearns and C. Wong for discussions; K. Polyak for showing us procedures with MMECs; A. D'Andrea, R. DePinho, M. Ewen, R. King, M. E. McLaughlin, K. Polyak and Z. Storchova for comments on the manuscript; J. Dunn for assistance with the figures; and S. Doxsey for the anti-pericentrin antibody. T.F. was a Uehara Memorial Foundation research fellow. D.P. was supported by an NIH grant and a scholar award from the Leukemia and Lymphoma Society of America.

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Correspondence to David Pellman.

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Supplementary information

Supplementary Figure S1

Characterization of viable cultures of diploid and tetraploid p53-/- MMECs (PDF 5085 kb)

Supplementary Figure S2

Tetraploid p53+/+ MMECs do not proliferate in vitro. (PDF 3309 kb)

Supplementary Figure S3

Genome-wide array-CGH analysis of tetraploid p53-/- MMECs hybridized to diploid MMECs. (PDF 711 kb)

Supplementary Figure S4

DCB does not induce DNA damage in p53-/- MMECs or wild-type p53+/+ MMECs. (PDF 3282 kb)

Supplementary Figure S5

DNA damage assessed by γ-H2AX labeling in p53-/-MMECs before and after FACS sorting. (PDF 2005 kb)

Supplementary Figure S6

Gross chromosomal rearrangements in tetraploid-derived transformed cells growing in soft agar (Figure 2). (PDF 517 kb)

Supplementary Figure S7

Characterization of the spontaneous tumors derived from tetraploid p53-/- MMECs. (PDF 11442 kb)

Supplementary Figure S8

Gross chromosomal rearrangements in the spontaneous tumors derived from tetraploid p53-/- MMECs. (PDF 301 kb)

Supplementary Figure S9

Genome-wide array-CGH analysis of 8 tumors derived from tetraploid p53-/- MMECs. (PDF 2838 kb)

Supplementary Figure 10

Genes on the amplicons identified from tetraploid-derived tumor. (PDF 356 kb)

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This file contains full text descriptions for all Supplementary Figures. (DOC 43 kb)

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Fujiwara, T., Bandi, M., Nitta, M. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005). https://doi.org/10.1038/nature04217

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