20. Increased Polo-like kinase 1 (Plk1) expression promotes centrosome amplification, chromosomal instability, and tumor formation in a mouse model

      Polo-like kinase 1 (PLK1) functions as a regulator of mitotic events. By completing a meta-analysis of The Cancer Genome Atlas, we determined that PLK1 overexpression is positively associated with genome-wide copy number alterations and a poorer prognosis in multiple human cancers. However, it is uncertain whether elevated PLK1 expression is a downstream marker for aggressive tumors or represents a driving force behind tumor progression. To address this question, we established a mouse model that ubiquitously express exogenous Plk1 in a graded manner [Plk1TA/+ (heterozygous) and Plk1TA/TA (homozygous)]. In early passage cells Plk1 overexpression promoted centrosome amplification, leading to chromosomal malsegregation and cytokinesis failure. Chromosomal instability (CIN) related to Plk1 overexpression was quantified by scoring: (1) micronuclei frequencies (MNF); and (2) metaphase spreads. Significant increases in MN were noted in both Plk1TA/+ (12%) and Plk1TA/TA (23%) cells, compared to wild type (WT) cells (2%). An analysis of mouse chromosomes showed aneuploidy in 23% of WT spreads, 65% of Plk1TA/+ and 75% of Plk1TA/TA cells, with chromosomal gains being seen most frequently. To determine if CIN was also present in neoplasms that originated from Plk1 transgenic mice, we analyzed metaphase spreads (GTG-banding) and interphase nuclei (FISH) from tumor specimens and identified significant increases in aneuploidy/polyploid cells. Moreover, we found that high levels of Plk1 expression compromised the DNA damage pathway, allowing cells with CIN to continue to proliferate and form “giant” multinucleated cells having polyploid complements. In summary, this study provides the first in vivo evidence that PLK1 is a potent proto-oncogene, that, when overexpressed, triggers CIN and tumorigenesis. This important finding highlights the involvement of PLK1 during the early stage of tumor development, and underscores the need for animal models that recapitulate the human scenario to enable investigators to gain further insight about the role of PLK1 in tumor formation/progression.
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