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Nucleic Acids Research Advance Access originally published online on September 19, 2008
Nucleic Acids Research 2008 36(18):5933-5945; doi:10.1093/nar/gkn586
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Nucleic Acids Research, 2008, Vol. 36, No. 18 5933-5945
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome integrity, repair and replication

Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots

Evagelos Liapis1,2, Keith I.E. McLuckie1, Paul D. Lewis3, Peter B. Farmer1 and Karen Brown1,*

1Department of Cancer Studies and Molecular Medicine, 2Department of Biochemistry, University of Leicester, Leicester, LE2 7LX and 3School of Medicine, Swansea University, South West Wales Cancer Institute, Singleton Hospital, Swansea, SA2 8QA, UK

*To whom correspondence should be addressed. Tel: +44 116 223 1851; Fax: +44 116 223 1855; Email: kb20{at}le.ac.uk

Received July 28, 2008. Revised August 29, 2008. Accepted August 29, 2008.

Tamoxifen elevates the risk of endometrial tumours in women and {alpha}-(N2-deoxyguanosinyl)-tamoxifen adducts are reportedly present in endometrial tissue of patients undergoing therapy. Given the widespread use of tamoxifen there is considerable interest in elucidating the mechanisms underlying treatment-associated cancer. Using a combined experimental and multivariate statistical approach we have examined the mutagenicity and potential consequences of adduct formation by reactive intermediates in target uterine cells. pSP189 plasmid containing the supF gene was incubated with {alpha}-acetoxytamoxifen or 4-hydroxytamoxifen quinone methide (4-OHtamQM) to generate dG-N2-tamoxifen and dG-N2-4-hydroxytamoxifen, respectively. Plasmids were replicated in Ishikawa cells then screened in Escherichia coli. Treatment with both {alpha}-acetoxytamoxifen and 4-OHtamQM caused a dose-related increase in adduct levels, resulting in a damage-dependent increase in mutation frequency for {alpha}-acetoxytamoxifen; 4-OHtamQM had no apparent effect. Only {alpha}-acetoxytamoxifen generated statistically different supF mutation spectra relative to the spontaneous pattern, with most mutations being GC->TA transversions. Application of the LwPy53 algorithm to the {alpha}-acetoxytamoxifen spectrum predicted strong GC->TA hotspots at codons 244 and 273. These signature alterations do not correlate with current reports of the mutations observed in endometrial carcinomas from treated women, suggesting that dG-N2-tam adduct formation in the p53 gene is not a prerequisite for endometrial cancer initiation in women.


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K. Brown
Is tamoxifen a genotoxic carcinogen in women?
Mutagenesis, September 1, 2009; 24(5): 391 - 404.
[Abstract] [Full Text] [PDF]


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