PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis

Polo-like kinase 1 (PLK1) is an essential cell-cycle regulator that is frequently overexpressed in various human cancers. To determine whether Plk1 overexpression drives tumorigenesis, we established transgenic mouse lines that ubiquitously express increased levels of Plk1. High Plk1 levels were a d...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2021-03, Vol.81 (5), p.1293-1307
Main Authors: Gheghiani, Lilia, Wang, Lei, Zhang, Youwei, Moore, Xavier T R, Zhang, Jinglei, Smith, Steven C, Tian, Yijun, Wang, Liang, Turner, Kristi, Jackson-Cook, Colleen K, Mukhopadhyay, Nitai D, Fu, Zheng
Format: Article
Language:English
Subjects:
Animals
Cell Cycle Checkpoints - genetics
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Proliferation - genetics
Cell Transformation, Neoplastic - genetics
Chromosomal Instability
Female
Gene Dosage
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms - genetics
Neoplasms - mortality
Polo-Like Kinase 1
Prognosis
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Proto-Oncogene Mas
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
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Summary:Polo-like kinase 1 (PLK1) is an essential cell-cycle regulator that is frequently overexpressed in various human cancers. To determine whether Plk1 overexpression drives tumorigenesis, we established transgenic mouse lines that ubiquitously express increased levels of Plk1. High Plk1 levels were a driving force for different types of spontaneous tumors. Increased Plk1 levels resulted in multiple defects in mitosis and cytokinesis, supernumerary centrosomes, and compromised cell-cycle checkpoints, allowing accumulation of chromosomal instability (CIN), which resulted in aneuploidy and tumor formation. Clinically, higher expression of PLK1 positively associated with an increase in genome-wide copy-number alterations in multiple human cancers. This study provides evidence that aberrant expression of PLK1 triggers CIN and tumorigenesis and highlights potential therapeutic opportunities for CIN-positive cancers. SIGNIFICANCE: These findings establish roles for PLK1 as a potent proto-oncogene and a CIN gene and provide insights for the development of effective treatment regimens across PLK1-overexpressing and CIN-positive cancers.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-20-1377