J Breast Cancer.
2022 Jun;25(3):178-192. 10.4048/jbc.2022.25.e28.
Polo-Like Kinase 1 Regulates Chromosomal Instability and Paclitaxel Resistance in Breast Cancer Cells
- Affiliations
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- 1Interdisciplinary Graduate Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea
- 2Medical Research Center, Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, Korea
- 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- 4Cancer Research Institute, Seoul National University, Seoul, Korea
- 5Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
- 6Department of Surgery, Seoul National University Hospital, Seoul, Korea
- 7Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
- KMID: 2530752
- DOI: http://doi.org/10.4048/jbc.2022.25.e28
Abstract
- Purpose
Chromosomal instability (CIN) contributes to intercellular genetic heterogeneity and has been implicated in paclitaxel (PTX) resistance in breast cancer. In this study, we explored polo-like kinase 1 (PLK1) as an important regulator of mitotic integrity and as a useful predictive biomarker for PTX resistance in breast cancer.
Methods
We performed PTX resistance screening using the human kinome CRISPR/ Cas9 library in breast cancer cells. In vitro cell proliferation and apoptosis assays and in vivo xenograft experiments were performed to determine the effects of PLK1 on breast cancer cells. Immunofluorescence microscopy was used to measure the degree of multipolar cell division.
Results
Kinome-wide CRISPR/Cas9 screening identified various kinases involved in PTX resistance in breast cancer cells; among these, PLK1 was chosen for further experiments. PLK1 knockdown inhibited the proliferation of MDA-MB-231 and MDA-MB-468 cells in vitro and in vivo. Moreover, PLK1 silencing sensitized breast cancer cells and mouse xenograft tumor models to PTX cytotoxicity. Silencing of PLK1 induced the formation of multipolar spindles and increased the percentage of multipolar cells. In addition, PLK1 silencing resulted in the downregulation of BubR1 and Mad2 in breast cancer cells. Furthermore, PLK1 upregulation in primary breast cancer was associated with decreased overall patient survival based on the analysis of The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium databases.
Conclusion
PLK1 plays an important role in PTX resistance by regulating CIN in breast cancer cells. Targeting PLK1 may be an effective treatment strategy for PTX-resistant breast cancers.
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