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Oxidative stress pathways highlighted in tumor cell immortalization: association with breast cancer outcome

Oncogene volume 26, pages 6269–6279 (2007)Cite this article

Abstract

An improved understanding of cell immortalization and its manifestation in clinical tumors could facilitate novel therapeutic approaches. However, only rare tumor cells, which maintain telomerase expression in vitro, immortalize spontaneously. By expression-profiling analyses of limited-life primary breast tumor cultures pre- and post-hTERT transduction, and spontaneously immortalized breast cancer cell lines, we identified a common signature characteristic of tumor cell immortalization. A predominant feature of this immortalization signature (ImmSig) was the significant overexpression of oxidoreductase genes. In contrast to epithelial cells derived from low histologic grade primary tumors, which required hTERT transduction for the acquisition of ImmSig, spontaneously immortalizing high-grade tumor cultures displayed similar molecular changes independent of exogenous hTERT. Silencing the hTERT gene reversed ImmSig expression, increased cellular reactive oxygen species levels, altered mitochondrial membrane potential and induced apoptotic and proliferation changes in immortalized cells. In clinical breast cancer samples, cell-proliferation-pathway genes were significantly associated with ImmSig. In these cases, ImmSig expression itself was inversely correlated with patient survival (P=0), and was particularly relevant to the outcome of estrogen receptor-positive tumors. Our data support the notion that ImmSig assists in surmounting normal barriers related to oxidative and replicative stress response. Targeting a subset of aggressive breast cancers by reversing ImmSig components could be a practical therapeutic strategy.

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Acknowledgements

We thank Dr Janos Demeter and Dr Wenzhong Xiao (Stanford University) for helpful suggestions on the Bioinformatic aspects of this study. This research was supported by NIH R01CA109325 (SHD), NIH K01 HG00030 (MN) and NIH U01 CA85129 (SSJ) and by funds from the California Breast Cancer Research Program of the University of California, grant numbers 8WB-0032 (SHD) and 10 EB-1086 (SSJ).

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Author notes

  1. M Nicolau

    Present address: 3Current address: M Nicolau, Department of Mathematics, Stanford University, Stanford, CA 94305, USA.,

  2. Y Ji

    Present address: 4Current address: Y Ji, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.,

  3. B Yong

    Present address: 5Current address: B Yong, Pfizer Pharmaceuticals Limited, 1168 Nan Jing Road, Shanghai 200041, PR China.,

Authors and Affiliations

  1. California Pacific Medical Center Research Institute, San Francisco, CA, USA

    S H Dairkee, A Sayeed, S Champion, D H Moore, B Yong & Z Meng

  2. Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA

    M Nicolau, Y Ji & S S Jeffrey

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  1. S H Dairkee
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Corresponding authors

Correspondence to S H Dairkee or S S Jeffrey.

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

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Dairkee, S., Nicolau, M., Sayeed, A. et al. Oxidative stress pathways highlighted in tumor cell immortalization: association with breast cancer outcome. Oncogene 26, 6269–6279 (2007). https://doi.org/10.1038/sj.onc.1210452

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