Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of Cdc20 suppresses the metastasis in triple negative breast cancer (TNBC)

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Cdc20 is a crucial activator of the anaphase-promoting complex (APC/C) and is known to be essential in mitosis regulation. Abnormally high expression of Cdc20 has been reported in several malignancies. We aimed to study the Cdc20 expression in human breast cancer tissues, focusing specifically on Cdc20 in Triple-Negative Breast Cancer (TNBC).

Methods

The expression of mitotic regulators mRNA in three TNBC cell lines or three other breast cancer cell lines was determined by the RNA-sequencing database. 14,713 human breast cancer patient samples included in Breast Cancer-GenExminer v4.5 were used to analyze whether cell division cycle 20 (Cdc20) expression was related to TNBC. To find whether Cdc20 expression impacted prognosis in TNBC, we used 2,249 TNBC patients database. The loss of Cdc20 by RNA interference (shRNA) and several mitotic inhibitors including Apcin, ZM447439, BI 2536, and VX-680 on the capacities of proliferation, migration, invasion were evaluated by colony-forming, wound-healing, transwell assay, and western blot, respectively.

Results

We studied the mitosis-related genes and proteins that are closely related to TNBC through the National Center for Biotechnology Information (NCBI) database. We found that Cdc20, one of the central mitotic regulators, is significantly upregulated in human TNBC, and its expression level is positively correlated with metastasis-free and relapse-free patient survival. We also found Cdc20 is highly conserved in TNBC in comparison to other breast cancer subtype cell lines. Cdc20 deficiency results in a decrease in cell growth and migration in four TNBC cell lines. Also, several mitotic inhibitors, such as Apcin, VX-680, ZM447439, and BI 2536, blocked cancer cell growth and invasion.

Conclusions

These results suggest an essential role of Cdc20 in tumor formation and metastasis of TNBC, which might be a potential target therapy for TNBC treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Dai X, Cheng H, Bai Z, Li J. Breast cancer cell line classification and its relevance with breast tumor subtyping. J Cancer. 2017;8:3131–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Medina MA, Oza G, Sharma A, Arriaga LG, Hernandez Hernandez JM, Rotello VM, et al. Triple-negative breast cancer: a review of conventional and advanced therapeutic strategies. Int J Environ Res Public Health. 2020;17:2078.

    Article  CAS  PubMed Central  Google Scholar 

  3. Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020;22:61.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Parise CA, Caggiano V. Breast cancer survival defined by the ER/PR/HER2 subtypes and a surrogate classification according to tumor grade and immunohistochemical biomarkers. J Cancer Epidemiol. 2014;2014:469251.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Lai CPT, Yeong JPS, Tan AS, Ong CHC, Lee B, Lim JCT, et al. Evaluation of phospho-histone H3 in Asian triple-negative breast cancer using multiplex immunofluorescence. Breast Cancer Res Treat. 2019;178:295–305.

    Article  CAS  PubMed  Google Scholar 

  6. Huang Y, Li W, Yan W, Wu J, Chen L, Yao X, et al. Loss of PICH promotes chromosome instability and cell death in triple-negative breast cancer. Cell Death Dis. 2019;10:428.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Marra A, Viale G, Curigliano G. Recent advances in triple negative breast cancer: the immunotherapy era. BMC Med. 2019;17:90.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Walsh EM, Keane MM, Wink DA, Callagy G, Glynn SA. Review of triple negative breast cancer and the impact of inducible nitric oxide synthase on tumor biology and patient outcomes. Crit Rev Oncog. 2016;21:333–51.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Xu J, Wu X, Zhou WH, Liu AW, Wu JB, Deng JY, et al. Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer. PLoS ONE. 2013;8:e56919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yu H. Cdc20: a WD40 activator for a cell cycle degradation machine. Mol Cell. 2007;27:3–16.

    Article  CAS  PubMed  Google Scholar 

  11. Wang L, Zhang J, Wan L, Zhou X, Wang Z, Wei W. Targeting Cdc20 as a novel cancer therapeutic strategy. Pharmacol Ther. 2015;151:141–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kapanidou M, Curtis NL, Bolanos-Garcia VM. Cdc20: At the Crossroads between chromosome segregation and mitotic exit. Trends Biochem Sci. 2017;42:193–205.

    Article  CAS  PubMed  Google Scholar 

  13. Karra H, Repo H, Ahonen I, Loyttyniemi E, Pitkanen R, Lintunen M, et al. Cdc20 and securin overexpression predict short-term breast cancer survival. Br J Cancer. 2014;110:2905–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee S, Zhang C, Liu X. Role of glucose metabolism and ATP in maintaining PINK1 levels during Parkin-mediated mitochondrial damage responses. J Biol Chem. 2015;290:904–17.

    Article  CAS  PubMed  Google Scholar 

  15. Shang G, Ma X, Lv G. Cell division cycle 20 promotes cell proliferation and invasion and inhibits apoptosis in osteosarcoma cells. Cell Cycle. 2018;17:43–52.

    Article  CAS  PubMed  Google Scholar 

  16. Wu WJ, Hu KS, Wang DS, Zeng ZL, Zhang DS, Chen DL, et al. CDC20 overexpression predicts a poor prognosis for patients with colorectal cancer. J Transl Med. 2013;11:142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhou Z, He M, Shah AA, Wan Y. Insights into APC/C: from cellular function to diseases and therapeutics. Cell Div. 2016;11:9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Kidokoro T, Tanikawa C, Furukawa Y, Katagiri T, Nakamura Y, Matsuda K. CDC20, a potential cancer therapeutic target, is negatively regulated by p53. Oncogene. 2008;27:1562–71.

    Article  CAS  PubMed  Google Scholar 

  19. Chang DZ, Ma Y, Ji B, Liu Y, Hwu P, Abbruzzese JL, et al. Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression. J Hematol Oncol. 2012;5:15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Richeson KV, Bodrug T, Sackton KL, Yamaguchi M, Paulo JA, Gygi SP, et al. Paradoxical mitotic exit induced by a small molecule inhibitor of APC/C(Cdc20). Nat Chem Biol. 2020;16:546–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sackton KL, Dimova N, Zeng X, Tian W, Zhang M, Sackton TB, et al. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature. 2014;514:646–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lub S, Maes A, Maes K, De Veirman K, De Bruyne E, Menu E, et al. Inhibiting the anaphase promoting complex/cyclosome induces a metaphase arrest and cell death in multiple myeloma cells. Oncotarget. 2016;7:4062–76.

    Article  PubMed  Google Scholar 

  23. Gully CP, Zhang F, Chen J, Yeung JA, Velazquez-Torres G, Wang E, et al. Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. Mol Cancer. 2010;9:42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Long ZJ, Xu J, Yan M, Zhang JG, Guan Z, Xu DZ, et al. ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture. Cell Cycle. 2008;7:1473–9.

    Article  CAS  PubMed  Google Scholar 

  25. Xu LZ, Long ZJ, Peng F, Liu Y, Xu J, Wang C, et al. Aurora kinase a suppresses metabolic stress-induced autophagic cell death by activating mTOR signaling in breast cancer cells. Oncotarget. 2014;5:7498–511.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Scutt PJ, Chu ML, Sloane DA, Cherry M, Bignell CR, Williams DH, et al. Discovery and exploitation of inhibitor-resistant aurora and polo kinase mutants for the analysis of mitotic networks. J Biol Chem. 2009;284:15880–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lenart P, Petronczki M, Steegmaier M, Di Fiore B, Lipp JJ, Hoffmann M, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 2007;17:304–15.

    Article  CAS  PubMed  Google Scholar 

  28. Steegmaier M, Hoffmann M, Baum A, Lenart P, Petronczki M, Krssak M, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17:316–22.

    Article  CAS  PubMed  Google Scholar 

  29. Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM, et al. Validating Aurora B as an anti-cancer drug target. J Cell Sci. 2006;119:3664–75.

    Article  CAS  PubMed  Google Scholar 

  30. Kim JJ, Lee SB, Jang J, Yi SY, Kim SH, Han SA, et al. WSB1 promotes tumor metastasis by inducing pVHL degradation. Genes Dev. 2015;29:2244–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 2003;100:8418–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006;7:96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160–7.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res. 2008;14:5158–65.

    Article  CAS  PubMed  Google Scholar 

  35. Wirapati P, Sotiriou C, Kunkel S, Farmer P, Pradervand S, Haibe-Kains B, et al. Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures. Breast Cancer Res. 2008;10:R65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Jezequel P, Frenel JS, Campion L, Guerin-Charbonnel C, Gouraud W, Ricolleau G, et al. bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses. Database (Oxford). 2013; 2013: bas060.

  37. Jezequel P, Campone M, Gouraud W, Guerin-Charbonnel C, Leux C, Ricolleau G, et al. bc-GenExMiner: an easy-to-use online platform for gene prognostic analyses in breast cancer. Breast Cancer Res Treat. 2012;131:765–75.

    Article  PubMed  Google Scholar 

  38. Levine MS, Holland AJ. The impact of mitotic errors on cell proliferation and tumorigenesis. Genes Dev. 2018;32:620–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018;553:467–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mondal G, Sengupta S, Panda CK, Gollin SM, Saunders WS, Roychoudhury S. Overexpression of Cdc20 leads to impairment of the spindle assembly checkpoint and aneuploidization in oral cancer. Carcinogenesis. 2007;28:81–92.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang Y, Li J, Yi K, Feng J, Cong Z, Wang Z, et al. Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma. Proc Natl Acad Sci U S A. 2019;116:6975–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fallahpour S, Navaneelan T, De P, Borgo A. Breast cancer survival by molecular subtype: a population-based analysis of cancer registry data. CMAJ Open. 2017;5:E734–9.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Jeibouei S, Akbari ME, Kalbasi A, Aref AR, Ajoudanian M, Rezvani A, et al. Personalized medicine in breast cancer: pharmacogenomics approaches. Pharmgenomics Pers Med. 2019;12:59–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. McCann KE, Hurvitz SA, McAndrew N. Advances in targeted therapies for triple-negative breast cancer. Drugs. 2019;79:1217–30.

    Article  PubMed  Google Scholar 

  45. Ponde NF, Zardavas D, Piccart M. Progress in adjuvant systemic therapy for breast cancer. Nat Rev Clin Oncol. 2019;16:27–44.

    Article  CAS  PubMed  Google Scholar 

  46. Stravodimou A, Voutsadakis IA. The future of ER+/HER2- metastatic breast cancer therapy: beyond PI3K inhibitors. Anticancer Res. 2020;40:4829–41.

    Article  CAS  PubMed  Google Scholar 

  47. Baak JP, van Diest PJ, Voorhorst FJ, van der Wall E, Beex LV, Vermorken JB, et al. Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years. J Clin Oncol. 2005;23:5993–6001.

    Article  PubMed  Google Scholar 

  48. Abdel-Fatah TM, Perry C, Dickinson P, Ball G, Moseley P, Madhusudan S, et al. Bcl2 is an independent prognostic marker of triple negative breast cancer (TNBC) and predicts response to anthracycline combination (ATC) chemotherapy (CT) in adjuvant and neoadjuvant settings. Ann Oncol. 2013;24:2801–7.

    Article  CAS  PubMed  Google Scholar 

  49. Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25:2677–81.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ingemarsdotter CK, Baird SK, Connell CM, Oberg D, Hallden G, McNeish IA. Low-dose paclitaxel synergizes with oncolytic adenoviruses via mitotic slippage and apoptosis in ovarian cancer. Oncogene. 2010;29:6051–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, et al. Capivasertib Plus Paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT Trial. J Clin Oncol. 2020;38:423–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the Jack Kent Cooke Foundation for providing support to experimentation and data analysis. We also thank Drs. Kathryn J. Ruddy, Roberto A. Leon-Ferre and Deb DeYoung for the editing of this paper. We also thank Zach Cohen (Jack Kent Cooke), Joanne Michet, Andrew Poterucha, Christin Stegenga, Alissa Naymark, Rhonda Hendrickson and JungJin Kim for their contribution in this paper.

Funding

This study was funded by the Jack Kent Cooke Foundation’s Young Scholars Program.

Author information

Authors and Affiliations

  1. Mayo High School, Rochester, MN, 55904, USA

    Christine Song

  2. Division of Radiology, Mayo Clinic, Rochester, MN, 55905, USA

    Val J. Lowe & SeungBaek Lee

  3. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA

    SeungBaek Lee

Authors
  1. Christine Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Val J. Lowe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. SeungBaek Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SBL and CS designed and performed most of the experiments, analyzed data, and prepared the manuscript as a lead author. VL contributed to editing and commenting on the paper. VL and SBL supervised the project.

Corresponding authors

Correspondence to Val J. Lowe or SeungBaek Lee.

Ethics declarations

Conflict of interest

Dr. Lowe is a consultant for AVID Radiopharmaceuticals, Eisai Co. Inc., Bayer Schering Pharma, GE Healthcare, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and NIH (NIA, NCI).

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 1105 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, C., Lowe, V.J. & Lee, S. Inhibition of Cdc20 suppresses the metastasis in triple negative breast cancer (TNBC). Breast Cancer 28, 1073–1086 (2021). https://doi.org/10.1007/s12282-021-01242-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-021-01242-z

Keywords

Search

Navigation