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Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells

Author

Listed:
  • Takeshi Fujiwara

    (Department of Pediatric Oncology)

  • Madhavi Bandi

    (Department of Pediatric Oncology)

  • Masayuki Nitta

    (Department of Pediatric Oncology)

  • Elena V. Ivanova

    (Dana-Farber Cancer Institute, Harvard Medical School)

  • Roderick T. Bronson

    (Tufts University Veterinary School)

  • David Pellman

    (Department of Pediatric Oncology
    Harvard Medical School)

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.

Suggested Citation

  • Takeshi Fujiwara & Madhavi Bandi & Masayuki Nitta & Elena V. Ivanova & Roderick T. Bronson & David Pellman, 2005. "Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells," Nature, Nature, vol. 437(7061), pages 1043-1047, October.
    • Handle: RePEc:nat:nature:v:437:y:2005:i:7061:d:10.1038_nature04217
    DOI: 10.1038/nature04217
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    Cited by:

    1. Chunyang Bao & Richard W. Tourdot & Gregory J. Brunette & Chip Stewart & Lili Sun & Hideo Baba & Masayuki Watanabe & Agoston T. Agoston & Kunal Jajoo & Jon M. Davison & Katie S. Nason & Gad Getz & Ken, 2023. "Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Revati Darp & Marc A. Vittoria & Neil J. Ganem & Craig J. Ceol, 2022. "Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Ellen B. Garcia & Cynthia Alms & Albert W. Hinman & Conor Kelly & Adam Smith & Marina Vance & Jadranka Loncarek & Linsey C. Marr & Daniela Cimini, 2019. "Single-Cell Analysis Reveals that Chronic Silver Nanoparticle Exposure Induces Cell Division Defects in Human Epithelial Cells," IJERPH, MDPI, vol. 16(11), pages 1-22, June.
    4. G. Yahya & P. Menges & P. S. Amponsah & D. A. Ngandiri & D. Schulz & A. Wallek & N. Kulak & M. Mann & P. Cramer & V. Savage & M. Räschle & Z. Storchova, 2022. "Sublinear scaling of the cellular proteome with ploidy," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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