Expression of TERT in early premalignant lesions and a subset of cells in normal tissues

Abstract

Activation of telomerase, the enzyme that synthesizes the telomere ends of linear chromosomes, has been implicated in human cell immortalization and cancer cell pathogenesis. Enzyme activity is undetectable in most normal cells and tissues, but present in immortal cells and cancer tissues1,2,3. While expression of TERC, the RNA component of telomerase, is widespread4,5,6, the restricted expression pattern of TERT, the telomerase catalytic subunit gene, is correlated with telomerase activity7,8,9, and its ectopic expression in telomerase-negative cells is sufficient to reconstitute telomerase activity10,11,12 and extend cellular lifespan13. We have used in situ hybridization to study TERT expression at the single-cell level in normal tissues and in various stages of tumour progression. In normal tissues, including some that are known to be telomerase-negative, TERT mRNA was present in specific subsets of cells thought to have long-term proliferative capacity. This included mitotically inactive breast lobular epithelium in addition to some actively regenerating cells such as the stratum basale of the skin. TERT expression appeared early during tumorigenesis in vivo, beginning with early pre-invasive changes in human breast and colon tissues and increasing gradually during progression, both in the amount of TERT mRNA present within individual cells and in the number of expressing cells within a neoplastic lesion. The physiological expression of TERT within normal epithelial cells that retain proliferative potential and its presence at the earliest stages of tumorigenesis have implications for the regulation of telomerase expression and for the identification of cells that may be targets for malignant transformation.

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Figure 1: Validation of in situ hybridization for TERTmRNA.
Figure 2: TERT expression in normal tissues.
Figure 3: TERT expression in colonic tumorigenesis.
Figure 4: TERT expression in breast carcinogenesis.

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Acknowledgements

We are grateful to L. Chen for technical assistance. This work was supported by National Institutes of Health Grants CA 68273 to W.L.G., CA 58596 to D.A.H. and OIG CA 39826 to R.A.W. K.A.K is supported by T32CA60376; L.W.E. is a fellow of the Howard Hughes Medical Institute; C.M.C is supported by the NCIC and the MIT-Merck postdoctoral fellowship; M.M. is supported by the Damon Runyon-Walter Winchell Cancer Research Foundation; R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.

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Correspondence to William L. Gerald.

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Kolquist, K., Ellisen, L., Counter, C. et al. Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet 19, 182–186 (1998). https://doi.org/10.1038/554

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