Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel

Scribano, Christina M.; Wan, Jun; Esbona, Karla; Tucker, John B.; Lasek, Amber; Zhou, Amber S.; Zasadil, Lauren M.; Molini, Ryan; Fitzgerald, Jonathan B.; Lager, Angela M.; Laffin, Jennifer; Correia-Staudt, Kayla; Wisinski, Kari B.; Tevaarwerk, Amye J.; O’Regan, Ruth; McGregor, Stephanie M.; Fowler, Amy M.; Chappell, Richard J.; Bugni, Tim S.; Burkard, Mark E.; Weaver, Beth A.

doi:10.1126/scitranslmed.abd4811

Cited by 79 publications

(81 citation statements)

References 46 publications

(76 reference statements)

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“…Chromosomal instability (CIN) leads to uncontrolled division of cells into tumors. However, scholars have recently proven that if this erroneous segregation is extreme, it can lead to cell death – the mechanism by which paclitaxel kills tumor cells by enlarging the chromosome segregation errors of tumor cells, thus overturning previous views [ 17 ]. The results indicated that these downregulated DEGs enriched in chromosome segregation and cell cycle pathways could act as target genes for aiding the effect of paclitaxel.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Key Pathways in Breast Cancer Based on Machine Learning

Bao

2022

Med Sci Monit

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Background Breast cancer is one of the most common malignant tumors among women worldwide. This study aimed to screen key genes and pathways for breast cancer diagnosis and treatment. Material/Methods We obtained public data from the NCBI GEO database. The data were divided into a control group (normal breast tissue) and a treatment group (breast cancer tissue). We screened 32 differentially expressed genes (DEGs) between normal breast and cancerous tissues and used GO analysis and GSEA to identify the key pathways. We then combined LASSO and SVM-RFE analyses to screen key genes, and used CIBERSORT to obtain the proportion of 22 types of immune cells. The relationships between key genes and immune-infiltrating cells were further explored. Results We screened 32 DEGs from the 2 groups, including 27 downregulated genes and 5 upregulated genes. GO analysis indicated that the DEGs were mainly correlated with collagen-containing extracellular matrix (ECM), Wnt signaling pathway, and glycosaminoglycan binding. GSEA indicated that the treatment group was correlated with chromosome segregation and cell cycle while the control group was correlated with cornification, intermediate filament, and nuclear transcription. Through machine learning, SYNM , TGFBR3 , and COL10A1 were screened as key genes. Numbers of CD8 T cells, gamma delta T cells, and M1 macrophages were significantly higher, while monocytes and follicular helper-T cells were significantly lower in the treatment group. The downregulated genes, SYNM and TGFBR3 , were positively correlated with CD8 T cells and monocytes, but were negatively correlated with gamma delta T cells and M1 macrophages. The upregulated gene, COL10A1 , was positively correlated with gamma delta T cells and M1 macrophages, and was negatively correlated with CD8 T cells, monocytes, and follicular helper-T cells. Conclusions SYNM , TGFBR3 , and COL10A1 are diagnostic genes of breast cancer. They affect breast cancer cells by modulating immune-infiltrating cells.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Key Pathways in Breast Cancer Based on Machine Learning

Bao

2022

Med Sci Monit

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“…Recent studies have suggested that PTX sensitivity is regulated by the degree of CIN in cancer [ 8 9 13 ]. To explore the association between PLK1 expression and CIN in breast cancer, we examined multipolar cell division using DNA, centrosome, and microtubule staining ( Supplementary Figure 2A and B ).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Extensive published data have shown that CIN is associated with PTX sensitivity in breast cancer [ 12 13 28 ]. CIN has recently been shown to increase PTX sensitivity in breast cancer cells [ 13 ]. CIN refers to errors in mitosis, including multipolar spindles, defects in mitotic spindle assembly, and improper kinetochore-microtubule attachment [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although several mechanisms of PTX resistance have been identified in breast cancer, such as alterations to tubulin structures, defects in the spindle assembly checkpoint (SAC), and dysregulation of several proteins, including P-glycoprotein and TP53, strategies to overcome these remain challenging [ 8 10 11 12 ]. Recently, emerging evidence has suggested that chromosomal instability (CIN) in breast cancer might serve as a predictor of PTX response [ 8 9 12 13 ]. Furthermore, recent studies have shown that CIN is associated with various malignant features of multiple types of human cancers [ 14 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Polo-Like Kinase 1 Regulates Chromosomal Instability and Paclitaxel Resistance in Breast Cancer Cells

Quan

Cho

et al. 2022

J Breast Cancer

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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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Individually Tailored Modular “Egg” Hydrogels Capable of Spatiotemporally Controlled Drug Release for Spinal Cord Injury Repair

Sun

Xiong

Yang

et al. 2023

Adv Healthcare Materials

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Controllable drug delivery systems (DDS) can overcome the disadvantages of conventional drug administration processes, such as high dosages or repeated administration. Herein, a smart DDS collagen hydrogel is deployed for spinal cord injury (SCI) repair based on modular designing of “egg” nanoparticles (NPs) that ingeniously accomplish controlled drug release via inducing a signaling cascade in response to external and internal stimuli. The “egg” NPs consist of a three‐layered structure: tannic acid/Fe3+/tetradecanol “eggshell,” zeolitic imidazolate framework‐8 (ZIF‐8) “egg white,” and paclitaxel “yolk.” Then NPs served as a crosslinking epicenter, blending with collagen solutions to generate functional hydrogels. Remarkably, the “eggshell” efficiently converts near‐infrared (NIR) irradiation into heat. Subsequently, tetradecanol can be triggered to disintegrate via heat, exposing the structure of ZIF‐8. The Zn‐imidazolium ion coordination bond of the “egg white” is susceptible to cleaving at the acidic SCI site, decomposing the skeleton to release paclitaxel on demand. As expected, the paclitaxel release rate upon NIR irradiation increased up to threefold on the seventh day, which matches endogenous neural stem/progenitor cell migration process. Taken together, the collagen hydrogels facilitate the neurogenesis and motor function recovery, demonstrating a revolutionary strategy for spatiotemporally controlled drug release and providing guidelines for the design of DDS.

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Chromosomal instability sensitizes patient breast tumors to multipolar divisions induced by paclitaxel

Abstract: Paclitaxel cytotoxicity in breast tumors depends on multipolar spindle maintenance and preexisting chromosomal instability.

Cited by 79 publications

References 46 publications

Identification of Key Genes and Key Pathways in Breast Cancer Based on Machine Learning

Identification of Key Genes and Key Pathways in Breast Cancer Based on Machine Learning

Polo-Like Kinase 1 Regulates Chromosomal Instability and Paclitaxel Resistance in Breast Cancer Cells

Individually Tailored Modular “Egg” Hydrogels Capable of Spatiotemporally Controlled Drug Release for Spinal Cord Injury Repair

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