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The expression of gene transcripts of telomere-associated genes in human breast cancer: correlation with clinico-pathological parameters and clinical outcome

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Abstract

Background: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres in human germ cells, embryogenesis and in cancer, maintaining chromosomal length, stability and cellular immortality. The hTERT gene is the rate-limiting determinant of telomerase reactivation during immortalization and malignant transformation. Telomeric DNA-binding proteins have been attracting increasing interest due to their essential role in the regulation of telomeric DNA length and in protecting against chromosomal end-to-end fusion. These proteins include hTR, TRF1, TRF2, TANK1, TANK2, POT1, TIN2, EST1, and TEP. This study represents the first comprehensive investigation of the mRNA expression of key telomere-related genes in human breast cancer.

Methods: One hundred and twenty seven tumour tissues and 33 normal tissues were analyzed. Levels of transcription of hTERT, hTR, TRF1, TRF2, TANK1, TANK2, POT1, TIN2, EST1, and TEP1 were determined using real-time quantitative PCR. The mRNA expression of these genes was normalized against CK19 and was then analyzed against the pathological parameters and clinical outcome over a 10 year follow up period.

Results: The mRNA expressions of hTERT, hTR, TANK1, EST1, and TEP1 were higher in tumour samples compared with normal breast tissue. This reached statistical significance for EST1 when comparing good prognosis tumours with normal breast tissue (means = 11013 vs 1160, P = 0.05). Both hTERT and TEP1 levels significantly predicted overall survival (P = 0.012 and 0.005 respectively) and disease-free survival (P = 0.0011 and 0.01 respectively).The mRNA levels of TANK2 and POT1 were lower in malignant tissues compared with non-malignant breast tissues and this difference reached statistical significance when comparing the levels in normal tissues with those in advanced tumours (P = 0.0008 and P = 0.038 respectively). Their levels fell further with increasing tumour’s stage and were higher in tumours from patients who remained disease free compared with those who developed local recurrence or distant metastasis or died from breast cancer.TRF2 showed a trend similar to that of TANK2 and POT1. Furthermore, there was a highly significant correlation between TANK1 expression and that of hTERT, hTR, TRF1, TRF2 and EST1, (r = 0.533, 0.586, 0.608, 0.644 and 0.551 respectively, P < 0.001).

Conclusions: Genes encoding telomere-associated proteins display different patterns of mRNA expression in human breast cancer, and in normal breast tissue, suggesting different and sometimes opposing roles in mammary carcinogenesis. hTERT, hTR, TANK1, EST1 and TEP1 seem to be up-regulated, with hTERT and TEP1 correlating with clinical outcome. Conversely, TANK2 and POT1 transcription levels demonstrate a compelling trend to be lower in malignant tissues and lower still in those patients who develop recurrent disease suggesting that TANK2 and POT1 may act as tumour suppressor genes possibly by negatively regulating telomerase activity.

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Acknowledgement

The authors would like to thank Dr Anthony Douglan-Jones for his expert help in histology and Mr Gareth Watkins for his help in cryosections. WGJ thanks the support by Cancer Research Wales (CRW) and Cancer Research UK (CR-UK). Support for RFN was provided by the European Commission 6th Framework project: LSHC-CT-2004–502943 (MOL CANCER MED).

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Authors and Affiliations

  1. St George’s University of London, Blackshaw Road, London, SW17 OQT, UK

    Mohamed Salhab & Kefah Mokbel

  2. Metastasis and Angiogenesis Research Group, University Department of Surgery, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK

    Wen G. Jiang

  3. The Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge, Middlesex, UB8 3PH, UK

    Robert F. Newbold & Kefah Mokbel

  4. The Princess Grace Hospital, 42-52 Nottingham Place, London, W1M 3FD, UK

    Kefah Mokbel

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Salhab, M., Jiang, W.G., Newbold, R.F. et al. The expression of gene transcripts of telomere-associated genes in human breast cancer: correlation with clinico-pathological parameters and clinical outcome. Breast Cancer Res Treat 109, 35–46 (2008). https://doi.org/10.1007/s10549-007-9622-8

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