Plk1 overexpression induces chromosomal instability and suppresses tumor development

Nat Commun. 2018 Aug 1;9(1):3012. doi: 10.1038/s41467-018-05429-5.

Abstract

Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge, in a Plk1 kinase-dependent manner. In vivo, Plk1 overexpression prevents the development of Kras-induced and Her2-induced mammary gland tumors, in the presence of increased rates of chromosome instability. In patients, Plk1 overexpression correlates with improved survival in specific breast cancer subtypes. Therefore, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor-suppressive properties by perturbing mitotic progression and cytokinesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Centrosome / metabolism
  • Chromosomal Instability / genetics*
  • Chromosome Segregation
  • Cytokinesis
  • Disease Models, Animal
  • Embryo, Mammalian / cytology
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Mice
  • Nuclear Proteins / metabolism
  • Oncogenes
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • Cep55 protein, human
  • Endosomal Sorting Complexes Required for Transport
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1