Skip to main content
SpringerLink
Log in

Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer

  • Short Communication
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

Ran GTPase regulates nuclear import, nuclear export, and mitotic spindle assembly. The multifunctional involvement of seventeen Ran GTPase components in these processes has complicated research into how each contributes to cancer development.

Objective

To assess whether individual and process-specific misexpression of Ran GTPase components contribute to chromosome instability (CIN) and worsen breast cancer patient prognosis.

Methods

Using publicly available datasets, we studied the degree of misexpression of all Ran GTPase signaling components in breast cancer, assessed their involvement in CIN and used four clinical tests to evaluate whether their misregulation may constitute independent prognostic predictors.

Results

A significant majority of Ran GTPase signaling components is overexpressed in breast cancer. Strikingly, spindle assembly components are overexpressed and associated with CIN with only marginal significance and four independent tests indicate that this does not worsen patient outcome. Overexpression of nuclear import components is neither CIN-associated nor clinically significant. In sharp contrast, overexpression of nuclear export components constitutes a strong independent marker for both CIN and poor patient prognosis. We identify Exportin 2/CSE1L, Exportin 3/XPOT, Exportin 5/XPO5, and RANBP1 as novel potential targets.

Conclusions

We find that overexpression of Ran GTPase components involved in nuclear export, but not nuclear import or mitotic spindle assembly, is a strong CIN-associated marker for poor breast cancer prognosis. This could mean that increased nuclear export (of, for instance, pRb, p53, p73, BRCA1, p21, p27, E2F4, IκB, survivin), rather than spindle defects, mainly drives CIN and tumorigenesis. Hence, selective inhibitors of nuclear export may be effective for treating the most aggressive and chromosomally unstable breast cancers.

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

References

  1. Ng CK, Pemberton HN, Reis-Filho JS. Breast cancer intratumor genetic heterogeneity: causes and implications. Expert Rev Anticancer Ther. 2012;12(8):1021–32.

    Article  CAS  PubMed  Google Scholar 

  2. Duijf PH, Schultz N, Benezra R. Cancer cells preferentially lose small chromosomes. Int J Cancer. 2013;132(10):2316–26.

    Article  CAS  PubMed  Google Scholar 

  3. Duijf PH, Benezra R. The cancer biology of whole-chromosome instability. Oncogene. 2013;32(40):4727–36.

    Article  CAS  PubMed  Google Scholar 

  4. Ganem NJ, Godinho SA, Pellman D. A mechanism linking extra centrosomes to chromosomal instability. Nature. 2009;460(7252):278–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Malmanche N, Maia A, Sunkel CE. The spindle assembly checkpoint: preventing chromosome mis-segregation during mitosis and meiosis. FEBS Lett. 2006;580(12):2888–95.

    Article  CAS  PubMed  Google Scholar 

  6. Thompson SL, Compton DA. Examining the link between chromosomal instability and aneuploidy in human cells. J Cell Biol. 2008;180(4):665–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Matchett KB, McFarlane S, Hamilton SE, Eltuhamy YS, Davidson MA, Murray JT, et al. Ran GTPase in nuclear envelope formation and cancer metastasis. Adv Exp Med Biol. 2014;773:323–51.

    Article  CAS  PubMed  Google Scholar 

  8. Arnaoutov A, Azuma Y, Ribbeck K, Joseph J, Boyarchuk Y, Karpova T, et al. Crm1 is a mitotic effector of Ran-GTP in somatic cells. Nat Cell Biol. 2005;7(6):626–32.

    Article  CAS  PubMed  Google Scholar 

  9. Joukov V, Groen AC, Prokhorova T, Gerson R, White E, Rodriguez A, et al. The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly. Cell. 2006;127(3):539–52.

    Article  CAS  PubMed  Google Scholar 

  10. Wang W, Budhu A, Forgues M, Wang XW. Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Nat Cell Biol. 2005;7(8):823–30.

    Article  CAS  PubMed  Google Scholar 

  11. Arnaoutov A, Dasso M. Ran-GTP regulates kinetochore attachment in somatic cells. Cell Cycle. 2005;4(9):1161–5.

    Article  CAS  PubMed  Google Scholar 

  12. Twyffels L, Gueydan C, Kruys V. Transportin-1 and Transportin-2: protein nuclear import and beyond. FEBS Lett. 2014;588(10):1857–68.

    Article  CAS  PubMed  Google Scholar 

  13. Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007;9(2):166–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

    Article  Google Scholar 

  16. Anders CK, Acharya CR, Hsu DS, Broadwater G, Garman K, Foekens JA, et al. Age-specific differences in oncogenic pathway deregulation seen in human breast tumors. PLoS One. 2008;3(1):e1373.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Buffa FM, Camps C, Winchester L, Snell CE, Gee HE, Sheldon H, et al. MicroRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res. 2011;71(17):5635–45.

    Article  CAS  PubMed  Google Scholar 

  18. Chanrion M, Negre V, Fontaine H, Salvetat N, Bibeau F, Mac Grogan G, et al. A gene expression signature that can predict the recurrence of tamoxifen-treated primary breast cancer. Clin Cancer Res. 2008;14(6):1744–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006;10(6):529–41.

    Article  CAS  PubMed  Google Scholar 

  20. Chin SF, Teschendorff AE, Marioni JC, Wang Y, Barbosa-Morais NL, Thorne NP, et al. High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol. 2007;8(10):R215.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, et al. Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res. 2007;13(11):3207–14.

    Article  CAS  PubMed  Google Scholar 

  22. Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res. 2011;17(18):6012–20.

    Article  CAS  PubMed  Google Scholar 

  23. Hatzis C, Pusztai L, Valero V, Booser DJ, Esserman L, Lluch A, et al. A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA. 2011;305(18):1873–81.

    Article  CAS  PubMed  Google Scholar 

  24. Jezequel P, Campone M, Roche H, Gouraud W, Charbonnel C, Ricolleau G, et al. A 38-gene expression signature to predict metastasis risk in node-positive breast cancer after systemic adjuvant chemotherapy: a genomic substudy of PACS01 clinical trial. Breast Cancer Res Treat. 2009;116(3):509–20.

    Article  CAS  PubMed  Google Scholar 

  25. Kao KJ, Chang KM, Hsu HC, Huang AT. Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization. BMC Cancer. 2011;11:143.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kuo WH, Chang YY, Lai LC, Tsai MH, Hsiao CK, Chang KJ, et al. Molecular characteristics and metastasis predictor genes of triple-negative breast cancer: a clinical study of triple-negative breast carcinomas. PLoS One. 2012;7(9):e45831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li Y, Zou L, Li Q, Haibe-Kains B, Tian R, Li Y, et al. Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer. Nat Med. 2010;16(2):214–8.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, et al. Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol. 2007;25(10):1239–46.

    Article  CAS  PubMed  Google Scholar 

  29. Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, Tutt AM, et al. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics. 2008;9:239.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436(7050):518–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, et al. Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci U S A. 2007;104(16):6740–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nagalla S, Chou JW, Willingham MC, Ruiz J, Vaughn JP, Dubey P, et al. Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. Genome Biol. 2013;14(4):R34.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, et al. Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res. 2005;7(6):R953–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, et al. The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 2008;68(13):5405–13.

    Article  CAS  PubMed  Google Scholar 

  35. Sircoulomb F, Bekhouche I, Finetti P, Adelaide J, Ben Hamida A, Bonansea J, et al. Genome profiling of ERBB2-amplified breast cancers. BMC Cancer. 2010;10:539.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A. 2003;100(18):10393–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999–2009.

    Article  PubMed  Google Scholar 

  38. Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet. 2005;365(9460):671–9.

    Article  CAS  PubMed  Google Scholar 

  39. Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG, et al. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res. 2005;65(20):9155–8.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang Y, Sieuwerts AM, McGreevy M, Casey G, Cufer T, Paradiso A, et al. The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy. Breast Cancer Res Treat. 2009;116(2):303–9.

    Article  CAS  PubMed  Google Scholar 

  41. Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, et al. Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer. 2007;7:59.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Shabalin AA, Tjelmeland H, Fan C, Perou CM, Nobel AB. Merging two gene-expression studies via cross-platform normalization. Bioinformatics. 2008;24(9):1154–60.

    Article  CAS  PubMed  Google Scholar 

  43. Ravdin PM, Siminoff LA, Davis GJ, Mercer MB, Hewlett J, Gerson N, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001;19(4):980–91.

    CAS  PubMed  Google Scholar 

  44. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet. 2006;38(9):1043–8.

    Article  CAS  PubMed  Google Scholar 

  45. Di Fiore B, Ciciarello M, Lavia P. Mitotic functions of the Ran GTPase network: the importance of being in the right place at the right time. Cell Cycle. 2004;3(3):305–13.

    Article  PubMed  Google Scholar 

  46. Turner JG, Dawson J, Sullivan DM. Nuclear export of proteins and drug resistance in cancer. Biochem Pharmacol. 2012;83(8):1021–32.

    Article  CAS  PubMed  Google Scholar 

  47. Rodriguez JA, Span SW, Ferreira CG, Kruyt FA, Giaccone G. CRM1-mediated nuclear export determines the cytoplasmic localization of the antiapoptotic protein Survivin. Exp Cell Res. 2002;275(1):44–53.

    Article  CAS  PubMed  Google Scholar 

  48. Parikh K, Cang S, Sekhri A, Liu D. Selective inhibitors of nuclear export (SINE)--a novel class of anti-cancer agents. J Hematol Oncol. 2014;7:78.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Manchado E, Guillamot M, Malumbres M. Killing cells by targeting mitosis. Cell Death Differ. 2012;19(3):369–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer. 2004;4(2):106–17.

    Article  CAS  PubMed  Google Scholar 

  51. Zhao J, Jin SB, Wieslander L. CRM1 and Ran are present but a NES-CRM1-RanGTP complex is not required in Balbiani ring mRNP particles from the gene to the cytoplasm. J Cell Sci. 2004;117(Pt 8):1553–66.

    Article  CAS  PubMed  Google Scholar 

  52. Pathria G, Garg B, Wagner C, Garg K, Gschaider M, Jalili A, et al. RanBP3 regulates melanoma cell proliferation via selective control of nuclear export. J Investig Dermatol. 2016;136(1):264–74.

    Article  CAS  PubMed  Google Scholar 

  53. Vajjhala PR, Macmillan E, Gonda T, Little M. The Wilms’ tumour suppressor protein, WT1, undergoes CRM1-independent nucleocytoplasmic shuttling. FEBS Lett. 2003;554(1–2):143–8.

    Article  CAS  PubMed  Google Scholar 

  54. Eleftheriou A, Yoshida M, Henderson BR. Nuclear export of human beta-catenin can occur independent of CRM1 and the adenomatous polyposis coli tumor suppressor. J Biol Chem. 2001;276(28):25883–8.

    Article  CAS  PubMed  Google Scholar 

  55. Thompson SL, Compton DA. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol. 2010;188(3):369–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Caestecker KW, Van de Walle GR. The role of BRCA1 in DNA double-strand repair: past and present. Exp Cell Res. 2013;319(5):575–87.

    Article  CAS  PubMed  Google Scholar 

  57. Schvartzman JM, Duijf PH, Sotillo R, Coker C, Benezra R. Mad2 is a critical mediator of the chromosome instability observed upon rb and p53 pathway inhibition. Cancer Cell. 2011;19(6):701–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Dr. Thu Nguyen for helpful discussions.

Author information

Authors and Affiliations

  1. The University of Queensland, University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia

    Srividya Vaidyanathan, Pulari U. Thangavelu & Pascal H. G. Duijf

Authors
  1. Srividya Vaidyanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pulari U. Thangavelu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pascal H. G. Duijf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pascal H. G. Duijf.

Ethics declarations

Funding

SV is supported by an International Postgraduate Research Scholarship and a University of Queensland (UQ) Centennial scholarship, PUT by UQ International, and UQ Diamantina Institute scholarships and PHGD by a fellowship from the National Breast Cancer Foundation and grants from UQ Diamantina Institute and UQ.

Conflict of Interest

SV, PUT and PHGD declare no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 143 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vaidyanathan, S., Thangavelu, P.U. & Duijf, P.H.G. Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer. Targ Oncol 11, 677–686 (2016). https://doi.org/10.1007/s11523-016-0432-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-016-0432-y

Keywords

Search

Navigation