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Accumulation and altered localization of telomere-associated protein TRF2 in immortally transformed and tumor-derived human breast cells

Oncogene volume 24, pages 3369–3376 (2005)Cite this article

Abstract

We have used cultured human mammary epithelial cells (HMEC) and breast tumor-derived lines to gain information on defects that occur during breast cancer progression. HMEC immortalized by a variety of agents (the chemical carcinogen benzo(a)pyrene, oncogenes c-myc and ZNF217, and/or dominant negative p53 genetic suppressor element GSE22) displayed marked upregulation (10–15 fold) of the telomere-binding protein, TRF2. Upregulation of TRF2 protein was apparently due to differences in post-transcriptional regulation, as mRNA levels remained comparable in finite lifespan and immortal HMEC. TRF2 protein was not upregulated by the oncogenic agents alone in the absence of immortalization, nor by expression of exogenously introduced hTERT genes. We found TRF2 levels to be at least twofold higher than in control cells in 11/15 breast tumor cell lines, suggesting that elevated TRF2 levels are a frequent occurrence during the transformation of breast tumor cells in vivo. The dispersed distribution of TRF2 throughout the nuclei in some immortalized and tumor-derived cells indicated that not all the TRF2 was associated with telomeres in these cells. The process responsible for accumulation of TRF2 in immortalized HMEC and breast tumor-derived cell lines may promote tumorigenesis by contributing to the cells’ ability to maintain an indefinite lifespan.

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Acknowledgements

We thank T de Lange for the TRF2 cDNA expression vector, and J Campisi for Tin2 antibodies as well as helpful discussions. This work was supported by grants from the National Institutes of Health (CA-24844), the California Breast Cancer Research Program (6JB-0133 and 8KB-0119), and the Department of Defense (DAMD17-02-1-0443), as well as by the Office of Energy Research, Office of Health and Biological Research, US Department of Energy under Contract No. DE-AC03-76SF00098. EB was supported by an NRSA fellowship (CA-108480) from the NIH. DG received additional support from the Indiana University Cancer Center, the American Cancer Society, an Indiana University School of Medicine Biomedical Research grant, and the Indiana Genomics Initiative (INGEN). INGEN of Indiana University is supported in part by Lilly Endowment, Inc.

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Authors and Affiliations

  1. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA

    Tarlochan Nijjar, Ekaterina Bassett, James Garbe, Martha R Stampfer & Paul Yaswen

  2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Yasuhiro Takenaka & David Gilley

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  1. Tarlochan Nijjar
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  2. Ekaterina Bassett
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  4. Yasuhiro Takenaka
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  5. Martha R Stampfer
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  7. Paul Yaswen
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Correspondence to David Gilley or Paul Yaswen.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

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Nijjar, T., Bassett, E., Garbe, J. et al. Accumulation and altered localization of telomere-associated protein TRF2 in immortally transformed and tumor-derived human breast cells. Oncogene 24, 3369–3376 (2005). https://doi.org/10.1038/sj.onc.1208482

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