1. Department of Pediatric Oncology and
2. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School,
3. Pediatric Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
4. Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, Massachusetts 01536, USA
5. *These authors contributed equally to this work

Correspondence to: David Pellman^1,3 Correspondence and requests for materials should be addressed to D.P. (Email: david_pellman@dfci.harvard.edu).

Abstract

A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies^{1, 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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