Tumor Biology

, Volume 37, Issue 9, pp 11917–11926 | Cite as

Shorter telomeres and high telomerase activity correlate with a highly aggressive phenotype in breast cancer cell lines

  • Hugo A. Ceja-Rangel
  • Patricia Sánchez-Suárez
  • Emilio Castellanos-Juárez
  • Rubicelia Peñaroja-Flores
  • Diego J. Arenas-Aranda
  • Patricio Gariglio
  • Luis Benítez-Bribiesca
Original Article


Maintenance of telomere length is one function of human telomerase that is crucial for the survival of cancer cells and cancer progression. Both telomeres and telomerase have been proposed as possible biomarkers of cancer risk and cancer invasiveness; however, their clinical relevance is still under discussion. In order to improve our understanding of the relationship between telomere length and telomerase activity with cancer invasiveness, we studied telomere length as well as telomerase levels, activity, and intracellular localization in breast cancer cell lines with diverse invasive phenotypes. We found an apparently paradoxical coincidence of short telomeres and enhanced telomerase activity in the most invasive breast cancer cell lines. We also observed that hTERT intracellular localization could be correlated with its level of activity. There was no association between human telomerase reverse transcriptase (hTERT) protein expression levels and invasiveness. We propose that simultaneous evaluation of these two biomarkers—telomere length and telomerase activity—could be useful for the assessment of the invasive capacity and aggressiveness of tumor cells from breast cancer patients.


Breast cancer Cell lines hTERT Telomerase activity Telomere length 



The authors thank Blanca Olivia Murillo Ortiz Ph. D. from IMSS Unidad Médica de Alta Especialidad #1 León, México, for her assistance in telomere length measuring assays; Enrique Perez Cárdenas Ph. D. from the Instituto Nacional de Cancerología, SSA, México for his support in invasion assays; and Carmen Mora Villalpando Ph. D. from IMSS Centro Médico Nacional Siglo XXI, México for her advice in qPCR assays. Hugo A. Ceja-Rangel is grateful for CONACYT-México and IMSS scholarships and is grateful for the support, advice, and tutorship of Dr. Luis Benítez Bribiesca and Dr. Patricio Gariglio.

Compliance with ethical standards


This study was supported with grants from the Coordination for Health Research, IMSS (FIS/IMSS/PROT/MD13/1253).

Conflicts of interest



  1. 1.
    Savage SA, Gadalla SM, Chanock SJ. The long and short of telomeres and cancer association studies. J Natl Cancer Inst. 2013;105(7):448–9.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Hou L, Zhang X, Gawron AJ, Liu J. Surrogate tissue telomere length and cancer risk: shorter or longer? Cancer Lett. 2012;319(2):130–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Blackburn EH. Structure and function of telomeres. Nature. 1991;350(6319):569–73.CrossRefPubMedGoogle Scholar
  4. 4.
    d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Frias C, Pampalona J, Genesca A, Tusell L. Telomere dysfunction and genome instability. Front Biosci (Landmark Ed). 2012;17:2181–96.CrossRefGoogle Scholar
  6. 6.
    Roger L, Jones RE, Heppel NH, Williams GT, Sampson JR, Baird DM. Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. J Natl Cancer Inst. 2013;105(16):1202211.CrossRefGoogle Scholar
  7. 7.
    Masuda A, Takahashi T. Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis. Oncogene. 2002;21(45):6884–97.CrossRefPubMedGoogle Scholar
  8. 8.
    Glybochko PV, Zezerov EG, Glukhov AI, Alyaev YG, Severin SE, Polyakovsky KA, et al. Telomerase as a tumor marker in diagnosis of prostatic intraepithelial neoplasia and prostate cancer. Prostate. 2014;74(10):1043–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Chen CH, Chen RJ. Prevalence of telomerase activity in human cancer. J Formos Med Assoc. 2011;110(5):275–89.CrossRefPubMedGoogle Scholar
  10. 10.
    Bisoffi M, Heaphy CM, Griffith JK. Telomeres: prognostic markers for solid tumors. Int J Cancer. 2006;119(10):2255–60.CrossRefPubMedGoogle Scholar
  11. 11.
    Svenson U, Roos G. Telomere length as a biological marker in malignancy. Biochim Biophys Acta. 2009;1792(4):317–23.CrossRefPubMedGoogle Scholar
  12. 12.
    Yu ST, Chen L, Wang HJ, Tang XD, Fang DC, Yang SM. hTERT promotes the invasion of telomerase-negative tumor cells in vitro. Int J Oncol. 2009;35(2):329–36.PubMedGoogle Scholar
  13. 13.
    Jaiswal RK, Kumar P, Yadava PK. Telomerase and its extracurricular activities. Cell Mol Biol Lett. 2013;18(4):538–54.CrossRefPubMedGoogle Scholar
  14. 14.
    Chen PC, Peng JR, Huang L, Li WX, Wang WZ, Cui ZQ, et al. Overexpression of human telomerase reverse transcriptase promotes the motility and invasiveness of HepG2 cells in vitro. Oncol Rep. 2013;30(3):1157–64.PubMedGoogle Scholar
  15. 15.
    Xu D, Wang Q, Gruber A, Björkholm M, Chen Z, Zaid A, et al. Downregulation of telomerase reverse transcriptase mRNA expression by wild-type p53 in human tumor cells. Oncogene. 2000;19(45):5123–33.CrossRefPubMedGoogle Scholar
  16. 16.
    Holliday DL, Speirs V. Choosing the right cell line for breast cancer research. Breast Cancer Res. 2011;13(4):215.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    O’Callaghan NJ, Fenech M. A quantitative PCR method for measuring absolute telomere length. Biol Proced Online. 2011;13:3.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Soussi T, Rubio-Nevado JM, Hamroun D and Béroud C. The p53 mutation handbook. Available online: www.htpp:// Accessed 17 July 2015.
  19. 19.
    Jeon BG, Kumar BM, Kang EJ, Ock SA, Lee SL, Kwack DO, et al. Characterization and comparison of telomere length, telomerase and reverse transcriptase activity and gene expression in human mesenchymal stem cells and cancer cells of various origins. Cell Tissue Res. 2011;345(1):149–61.CrossRefPubMedGoogle Scholar
  20. 20.
    Motevalli A, Yasaei H, Virmouni SA, Slijepcevic P, Roberts T. The effect of chemotherapeutic agents on telomere length maintenance in breast cancer cell lines. Breast Cancer Res Treat. 2014;145(3):581–91.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Sakin V, Eskiocak U, Kars MD, Iseri OD, Gunduz U. hTERT gene expression levels and telomerase activity in drug resistant MCF-7 cells. Exp Oncol. 2008;30(3):202–5.PubMedGoogle Scholar
  22. 22.
    Kammori M, Sugishita Y, Okamoto T, Kobayashi M, Yamazaki K, Yamada E, et al. Telomere shortening in breast cancer correlates with the pathological features of tumor progression. Oncol Rep. 2015;34(2):627–32.PubMedGoogle Scholar
  23. 23.
    O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2010;11:171–81.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Martinez-Delgado B, Gallardo M, Tanic M, Yanowsky K, Inglada-Perez L, Barroso A, et al. Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade. Breast Cancer Res Treat. 2013;141(2):231–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Kulić A, Plavetić ND, Gamulin S, et al. Telomerase activity in breast cancer patients: association with poor prognosis and more aggressive phenotype. Med Oncol. 2016;33(3):23.CrossRefPubMedGoogle Scholar
  26. 26.
    Jeong SA, Kim K, Lee JH, Cha JS, Khadka P, Cho HS, et al. Akt mediated phosphorylation increases the binding affinity of hTERT for import in α to promote nuclear translocation. J Cell Sci. 2015;128(12):2287–301.CrossRefPubMedGoogle Scholar
  27. 27.
    Gupta A, Sharma S, Reichenbach P, Marjavaara L, Nilsson AK, Lingner J, et al. Telomere length homeostasis responds to changes in intracellular dNTP pools. Genetics. 2013;193(4):1095–105.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Podlevsky JD, Chen JJ. It all comes together at the ends: telomerase structure, function, and biogenesis. Mutat Res. 2012;730(1–2):3–11.CrossRefPubMedGoogle Scholar
  29. 29.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lukashchuk N, Vousden KH. Ubiquitination and degradation of mutant p53. Mol Cell Biol. 2007;27(23):8284–95.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, et al. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature. 2015;525(7568):206–11.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Benson CS, Babu SD, Radhakrishna S, Selvamurugan N, Ravi SB. Expression of matrix metalloproteinases in human breast cancer tissues. Dis Markers. 2013;34(6):395–405.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Eiró N, Fernandez-Garcia B, González LO, Vizoso FJ. Clinical relevance of matrix metalloproteases and their inhibitors in breast cancer. J Carcinog Mutagen. 2013;S13:004.Google Scholar
  34. 34.
    Ding D, Xi P, Zhou J, Wang M, Cong YS. Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NF-κB-dependent transcription. FASEB J. 2013;27(11):4375–83.CrossRefPubMedGoogle Scholar
  35. 35.
    Mannello F, Medda V. Nuclear localization of matrix metalloproteinases. Prog Histochem Cytochem. 2012;47(1):27–58.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Hugo A. Ceja-Rangel
    • 1
    • 2
  • Patricia Sánchez-Suárez
    • 2
  • Emilio Castellanos-Juárez
    • 2
  • Rubicelia Peñaroja-Flores
    • 2
  • Diego J. Arenas-Aranda
    • 3
  • Patricio Gariglio
    • 1
  • Luis Benítez-Bribiesca
    • 2
  1. 1.Departamento de Genética y Biología MolecularCentro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV)Ciudad de MéxicoMexico
  2. 2.Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de OncologíaCentro Médico Nacional Siglo XXI Instituto Mexicano del Seguro SocialCiudad de MéxicoMexico
  3. 3.Unidad de Investigación Médica en Genética Humana, Hospital de PediatríaCentro Médico Nacional Siglo XXI Instituto Mexicano del Seguro SocialCiudad de MéxicoMexico

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