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Functional characterization of novel presenilin-2 variants identified in human breast cancers

Oncogene volume 25, pages 3557–3564 (2006)Cite this article

Abstract

We identified in breast cancer cases two germline alterations, R62H and R71W, in presenilin-2 (PS-2), a gene involved in familial Alzheimer's disease (FAD). The role of these alleles in FAD is unclear, but neither allele affected Aβ(42)/Aβ(40) ratio. However, both R62H and R71W alterations compromised PS-2 function in Notch signaling in Caenorhabditis elegans and cell growth inhibition in mouse embryonic fibroblasts, and these effects were dependent on gene dosage. We found that both alterations enhanced the degradation of the PS-2 full-length protein, indicating that they may have a loss-of function effect. The effect of the R71W alteration was noticeably stronger, and we observed an almost threefold higher frequency of this allele in breast cancer cases versus controls, but this difference did not reach statistical significance. Nonetheless, these results collectively suggest that the novel PS-2 alleles described here, especially R71W, affect PS-2 function and may potentially confer a moderate risk of susceptibility to breast cancer.

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Acknowledgements

PS-2 antibodies were generous gifts of Drs P Mathews, G Thinakaran, P Davies and P Fraser. We are grateful to S Bull, R Parkes and Dushanthi Pinnaduwage for assistance with statistical analyses, and P Ray for DNA specimens. This work was funded by the USAMRMC with fellowship to MDT, the Canadian Breast Cancer Research Initiative (ILA, JK), the National Cancer Institute of Canada with funds provided by the Terry Fox Run (ILA) and NCI/NIH (U01 CA69467 (ILA)).

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Author notes

  1. M D To

    Present address: UCSF Comprehensive Cancer Center, San Francisco, CA, 94115, USA

  2. D B Donoviel

    Present address: Lexicon Genetics Inc., The Woodlands, TX, 77381, USA

Authors and Affiliations

  1. Fred A Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    M D To, N Gokgoz, D B Donoviel, A Bernstein & I L Andrulis

  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

    M D To, A Bernstein & I L Andrulis

  3. Integrated Program of Cellular, Molecular, and Biophysical Studies, Columbia University, New York, NY, USA

    T G Doyle

  4. Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    J A Knight

  5. Deparment of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada

    J A Knight

  6. Centre for Research into Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada

    P S Hyslop

  7. Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada

    P S Hyslop

  8. Canadian Institutes of Health Research, Ottawa, Ontario, Canada

    A Bernstein

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Correspondence to I L Andrulis.

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To, M., Gokgoz, N., Doyle, T. et al. Functional characterization of novel presenilin-2 variants identified in human breast cancers. Oncogene 25, 3557–3564 (2006). https://doi.org/10.1038/sj.onc.1209397

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