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 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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Polyploidy is considered a prerequisite to aneuploidy.
“Polyploidy is considered a prerequisite to aneuploidy (Fujiwara et al., 2005, Ganem et al., 2007, Storchova and Kuffer, 2008, Thompson et al., 2010, Vitale et al., 2010)”
From Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression (2011) · cites this paper as Fujiwara et al., 2005
The polyploidy observed in Mdm2 transgenic cells is likely due at least in part to inhibition of p53 by Mdm2.
“Since Mdm2 negatively regulates p53 (Marine and Lozano, 2010), and p53 inhibits the development of tetraploidy (Fujiwara et al., 2005, Ganem et al., 2007, Storchova and Kuffer, 2008, Thompson et al., 2010, Vitale et al., 2010), the polyploidy we observed in Mdm2 transgenic cells is likely due at least in part to inhibition of p53 by Mdm2.”
From Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression (2011) · cites this paper as Fujiwara et al., 2005
Cites
New functions for the matrix metalloproteinases in cancer progression
Egeblad, M., & Werb, Z. (2002) · Nature Reviews Cancer · doi:10.1038/nrc745 · Cited by 6,108 · see citing works
Met, metastasis, motility and more
Birchmeier, C., Birchmeier, W., Gherardi, E., & Woude, G. V. (2003) · Nature reviews. Molecular cell biology · doi:10.1038/nrm1261 · Cited by 2,667 · see citing works
Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53
Livingstone, L. R., White, A., Sprouse, J., Livanos, E., Jacks, T., & Tlsty, T. D. (1992) · Cell · doi:10.1016/0092-8674(92)90243-6 · Cited by 1,333 · see citing works
Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice
Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., & DePinho, R. A. (2000) · Nature · doi:10.1038/35020592 · Cited by 1,085 · see citing works
Effects of Cytochalasins on Mammalian Cells
CARTER, S. B. (1967) · Nature · doi:10.1038/213261a0 · Cited by 951 · see citing works
From polyploidy to aneuploidy, genome instability and cancer
Štorchová, Z., & Pellman, D. S. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1276 · Cited by 810 · see citing works
Self-citationThe Function and Mechanism of Promoters of Carcinogenesis
Boutwell, R. K., & Sivak, A. J. (1973) · Critical Reviews in Toxicology · doi:10.3109/10408447309025704 · Cited by 750 · see citing works
Centrosome aberrations: cause or consequence of cancer progression?
Nigg, E. A. (2002) · Nature reviews. Cancer · doi:10.1038/nrc924 · Cited by 733 · see citing works
Centrosome amplification drives chromosomal instability in breast tumor development
Lingle, W. L., Barrett, S. L., Negron, V. C., D’Assoro, A. B., Boeneman, K., Liu, W., Whitehead, C. M., Reynolds, C. A., & Salisbury, J. L. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.032479999 · Cited by 577 · see citing works
Bassing, C. H., Suh, H., Ferguson, D. O., Chua, K. F., Manis, J. P., Eckersdorff, M., Gleason, M., Bronson, R. T., Lee, C., & Alt, F. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00566-x · Cited by 480 · see citing works
Self-citationChromosome segregation and cancer: cutting through the mystery
Jallepalli, P. V., & Christoph Lengauer, C. (2001) · Nature reviews. Cancer · doi:10.1038/35101065 · Cited by 464 · see citing works
Tetraploid State Induces p53-dependent Arrest of Nontransformed Mammalian Cells in G1
Andreassen, P. R., Lohez, O. D., Lacroix, F., & Margolis, R. L. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.5.1315 · Cited by 429 · see citing works
Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines
Shi, Q., & King, R. W. (2005) · Nature · doi:10.1038/nature03958 · Cited by 396 · see citing works
Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas.
Pihan, G. A., Wallace, J., Zhou, Y., & Doxsey, S. (2003) · PubMed · Cited by 373 · see citing works
Galipeau, P. C., Cowan, D., Sanchez, C. A., Barrett, M. T., Emond, M. J., Levine, D. S., Rabinovitch, P. S., & Reid, B. J. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.14.7081 · Cited by 360 · see citing works
(1929) · Archives of Internal Medicine · doi:10.1001/archinte.1929.00140060125019 · Cited by 328 · see citing works
Abnormal Cytokinesis in Cells Deficient in the Breast Cancer Susceptibility Protein BRCA2
Daniels, M. J., Wang, Y., Lee, M.-Y., et al. (2004) · Science · doi:10.1126/science.1102574 · Cited by 319 · see citing works
Tetraploidy and chromosomal instability are early events during cervical carcinogenesis
Olaharski, A. J., Sotelo, R., Solorza-Luna, G., Gonsebatt, M. E., Guzmán, P., Mohar, A., & Eastmond, D. A. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi218 · Cited by 264 · see citing works
Model for the genetic evolution of human solid tumors.
Shackney, S. E., Smith, C., Miller, B. W., Burholt, D. R., Murtha, K., Giles, H. R., Ketterer, D. M., & Pollice, A. A. (1989) · PubMed · Cited by 252 · see citing works
Telomere dysfunction and the initiation of genome instability
Feldser, D. M., Hackett, J. A., & Greider, C. W. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1142 · Cited by 223 · see citing works
Cell cycle progression after cleavage failure
Uetake, Y., & Sluder, G. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403014 · Cited by 203 · see citing works
LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1
Yang, X., Yu, K.-P., Hao, Y., et al. (2004) · Nature Cell Biology · doi:10.1038/ncb1140 · Cited by 188 · see citing works
High levels of chromosome instability in polyploids of Saccharomyces cerevisiae
Mayer, V. W., & Aguilera, A. (1990) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/0027-5107(90)90024-x · Cited by 160 · see citing works
High-Resolution Global Profiling of Genomic Alterations with Long Oligonucleotide Microarray
Brennan, C. W., Zhang, Y., Leo, C., Feng, B., Cauwels, C., Aguirre, A. J., Kim, M., Protopopov, A. I., & Chin, L. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1241 · Cited by 150 · see citing works
Wong, C., & Stearns, T. (2005) · BMC Cell Biology · doi:10.1186/1471-2121-6-6 · Cited by 136 · see citing works
Levine, D. S., Sanchez, C. A., Rabinovitch, P. S., & Reid, B. J. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.15.6427 · Cited by 134 · see citing works
Polyploids require Bik1 for kinetochore–microtubule attachment
Lin, H., Carvalho, P., Kho, D., Tai, C., Pierre, P., Fink, G. R., & Pellman, D. S. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200108119 · Cited by 102 · see citing works
Self-citationMurphy, K. L., Dennis, A. P., & Rosen, J. M. (2000) · The FASEB Journal · doi:10.1096/fj.00-0128com · Cited by 91 · see citing works
David, G., Turner, G. M., Yao, Y., Protopopov, A. I., & DePinho, R. A. (2003) · Genes & Development · doi:10.1101/gad.1109403 · Cited by 89 · see citing works
Triggering p53 after cytokinesis failure
Stukenberg, P. T. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200405089 · Cited by 62 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Clonal heterogeneity and tumor evolution: past, present, and the future
McGranahan, N., & Swanton, C. (2017) · Cell · doi:10.1016/j.cell.2017.01.018 · Cited by 2,840 · see citing works
Tracking the Evolution of Non–Small-Cell Lung Cancer
Jamal-Hanjani, M., Wilson, G. A., McGranahan, N., Birkbak, N. J., Watkins, T. B. K., Veeriah, S., Shafi, S., Johnson, D. H., Mitter, R., Rosenthal, R., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1616288 · Cited by 2,349 · see citing works
DNA breaks and chromosome pulverization from errors in mitosis
Crasta, K., Ganem, N. J., Dagher, R., Lantermann, A. B., Ivanova, E. V., Pan, Y., Nezi, L., Protopopov, A., Chowdhury, D., & Pellman, D. (2012) · Nature · doi:10.1038/nature10802 · Cited by 1,227 · see citing works
Self-citationBoveri revisited: chromosomal instability, aneuploidy and tumorigenesis
Holland, A. J., & Cleveland, D. W. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2718 · Cited by 859 · see citing works
Telomeres in cancer: tumour suppression and genome instability
Maciejowski, J., & de Lange, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.171 · Cited by 745 · see citing works
Tetraploidy, aneuploidy and cancer
Ganem, N. J., Storchova, Z., & Pellman, D. (2007) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2007.02.011 · Cited by 668 · see citing works
Self-citationMechanisms generating cancer genome complexity from a single cell division error
Umbreit, N. T., Zhang, C.-Z., Lynch, L. D., Blaine, L. J., Cheng, A. M., Tourdot, R., Sun, L., Almubarak, H. F., Judge, K., Mitchell, T. J., et al. (2020) · Science · doi:10.1126/science.aba0712 · Cited by 439 · see citing works
Self-citationAn Immunosurveillance Mechanism Controls Cancer Cell Ploidy
Senovilla, L., Vitale, I., Martins, I., Tailler, M., Pailleret, C., Michaud, M., Galluzzi, L., Adjemian, S., Kepp, O., Niso-Santano, M., et al. (2012) · Science · doi:10.1126/science.1224922 · Cited by 436 · see citing works
The consequences of tetraploidy and aneuploidy
Storchova, Z., & Kuffer, C. (2008) · Journal of Cell Science · doi:10.1242/jcs.039537 · Cited by 363 · see citing works
Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy
Davoli, T., Denchi, E. L., & de Lange, T. (2010) · Cell · doi:10.1016/j.cell.2010.01.031 · Cited by 298 · see citing works
Davoli, T., & de Lange, T. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.044 · Cited by 242 · see citing works
Ordered and deterministic cancer genome evolution after p53 loss
Baslan, T., Morris, J. P., Zhao, Z., Reyes, J., Ho, Y.-J., Tsanov, K. M., Bermeo, J., Tian, S., Zhang, S., Askan, G., et al. (2022) · Nature · doi:10.1038/s41586-022-05082-5 · Cited by 221 · see citing works
Distinct roles of septins in cytokinesis: SEPT9 mediates midbody abscission
Estey, M. P., Di Ciano-Oliveira, C., Froese, C. D., Bejide, M. T., & Trimble, W. S. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201006031 · Cited by 231 · see citing works
A Tetraploid Intermediate Precedes Aneuploid Formation in Yeasts Exposed to Fluconazole
Harrison, B. D., Hashemi, J., Bibi, M., Pulver, R., Bavli, D., Nahmias, Y., Wellington, M., Sapiro, G., & Berman, J. (2014) · PLoS Biology · doi:10.1371/journal.pbio.1001815 · Cited by 174 · see citing works
A non-genetic route to aneuploidy in human cancers
Krajcovic, M., Johnson, N. B., Sun, Q., Normand, G., Hoover, N., Yao, E., Richardson, A. L., King, R. W., Cibas, E. S., Schnitt, S. J., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2174 · Cited by 188 · see citing works
Polyploid titan cells produce haploid and aneuploid progeny to promote stress adaptation
Gerstein, A. C., Fu, M. S., Mukaremera, L., Li, Z., Ormerod, K. L., Fraser, J. A., Berman, J., & Nielsen, K. (2015) · mBio · doi:10.1128/mbio.01340-15 · Cited by 167 · see citing works
The Polyploid State Plays a Tumor-Suppressive Role in the Liver
Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H.-C., Sehgal, A., Nguyen, L. H., Zhang, Y., Gopal, P., Tarlow, B. D., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.010 · Cited by 180 · see citing works
Illicit survival of cancer cells during polyploidization and depolyploidization
Vitale, I., Galluzzi, L., Senovilla, L., Criollo, A., Jemaà, M., Castedo, M., & Kroemer, G. (2011) · Cell Death & Differentiation · doi:10.1038/cdd.2010.145 · Cited by 159 · see citing works
Eischen, C. M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026096 · Cited by 161 · see citing works
Multipolar mitosis of tetraploid cells: inhibition by p53 and dependency on Mos
Vitale, I., Senovilla, L., Jemaà, M., Michaud, M., Galluzzi, L., Kepp, O., Nanty, L., Criollo, A., Rello‐Varona, S., Manic, G., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.11 · Cited by 146 · see citing works
Ploidy Variation in Fungi: Polyploidy, Aneuploidy, and Genome Evolution
Todd, R. T., Forche, A., & Selmecki, A. (2017) · Microbiology Spectrum · doi:10.1128/microbiolspec.funk-0051-2016 · Cited by 121 · see citing works
Mechanisms and consequences of entosis
Krishna, S., & Overholtzer, M. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2207-0 · Cited by 118 · see citing works
Cancer Genomes Evolve by Pulverizing Single Chromosomes
Meyerson, M., & Pellman, D. (2011) · Cell · doi:10.1016/j.cell.2010.12.025 · Cited by 115 · see citing works
Self-citationMechanisms of Ploidy Increase in Human Cancers: A New Role for Cell Cannibalism
Krajcovic, M., & Overholtzer, M. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3127 · Cited by 102 · see citing works
Inhibition of Chk1 Kills Tetraploid Tumor Cells through a p53-Dependent Pathway
Vitale, I., Galluzzi, L., Vivet, S., Nanty, L., Dessen, P., Senovilla, L., Olaussen, K. A., Lazar, V., Prudhomme, M., Golsteyn, R. M., et al. (2007) · PLoS ONE · doi:10.1371/journal.pone.0001337 · Cited by 77 · see citing works
Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis
Gascoigne, K. E., & Cheeseman, I. M. (2013) · Chromosome Research · doi:10.1007/s10577-013-9368-6 · Cited by 65 · see citing works
PTEN regulates PLK1 and controls chromosomal stability during cell division
Zhang, Z., Hou, S.-Q., He, J., Gu, T., Yin, Y., & Shen, W. H. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1203493 · Cited by 46 · see citing works
Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression
Lushnikova, T., Bouska, A., Odvody, J., Dupont, W. D., & Eischen, C. M. (2011) · Oncogene · doi:10.1038/onc.2011.172 · Cited by 40 · see citing works
The origins and functions of hepatic polyploidy
Zhang, S., Lin, Y.-H., Tarlow, B., & Zhu, H. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1618123 · Cited by 38 · see citing works
Karyotypic Aberrations in Oncogenesis and Cancer Therapy
Vitale, I., Manic, G., Senovilla, L., Kroemer, G., & Galluzzi, L. (2015) · Trends in Cancer · doi:10.1016/j.trecan.2015.08.001 · Cited by 34 · see citing works
- Authors
- Fujiwara, T., Bandi, M., Nitta, M., Ivanova, E. V., Bronson, R. T., & Pellman, D.
- Affiliations
- Harvard University (US)
- Tufts University (US)
- Corresponding author
- Pellman, David
- Venue
- Nature
- Published
- 2005-10-13
- Volume
- 437
- Issue
- 7061
- Pages
- 1043-1047
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1970442105
- Cited by
- 1,067
- References
- 30
- Citations by year
- 2026: 28 · 2025: 35 · 2024: 46 · 2023: 53 · 2022: 51 · 2021: 59 · 2020: 44 · 2019: 46 · 2018: 65 · 2017: 62 · 2016: 59 · 2015: 69 · 2014: 37 · 2013: 58 · 2012: 76
- FWCI
- 17.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- cytokinesis failure, tetraploidy, carcinogenesis, p53-null cells, mammary epithelial cells, chromosomal rearrangements, non-reciprocal translocation, carcinogen-induced transformation, mammary tumors, chromosomal instability
- MeSH terms
- Animals, Cell Survival, Cell Transformation, Neoplastic, Chromosome Aberrations, Epithelial Cells, Female, Mammary Glands, Animal, Mice, Nude, Myoepithelioma, Polyploidy, Genes, p53, Tumor Suppressor Protein p53, Cell Transplantation, Matrix Metalloproteinases, Cytokinesis, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
