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Human sebaceous tumors harbor inactivating mutations in LEF1

Abstract

We found that one-third of human sebaceous tumors examined had double-nucleotide substitutions in the same LEF1 allele, irrespective of DNA mismatch repair status. The mutations impaired both LEF1 binding to β-catenin and transcriptional activation, and are the first tumor-associated mutations that inactivate Wnt signaling. Mutant LEF1 not only inhibited expression of β-catenin target genes but also stimulated expression of sebocyte markers, suggesting that it may determine the differentiated characteristics of sebaceous tumors.

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Figure 1: Identification of LEF1 mutations in human sebaceous tumors and their effect on β-catenin transcriptional activity.
Figure 2: Effects of LEF1 mutations on binding to β-catenin and sebocyte gene expression.

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Acknowledgements

We are grateful to the Cancer Research UK (CR-UK) Equipment Park staff for technical assistance with sequencing. We thank P. Bates and B. Ponder for comments, and M. van de Wetering and C. Lo Celso for reagents. This work was supported by CR-UK (to H.T., I.S. and F.M.W.), US National Institutes of Health grant AR02179 (to S.L.), Harvard Skin Disease Research Center grant P30AR042689 (to A.J.F.L.) and a Uehara Memorial Foundation Fellowship (to H.T.). C.C.Z.'s contribution to this work was to provide SZ95 cells; he is a co-author under the terms of a Materials Transfer Agreement with F.M.W.

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Correspondence to Fiona M Watt.

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Competing interests

Christos C. Zouboulis is the owner of the patents 'Sebocytes, sebocyte cell line and uses thereof' EP1151082, DE19903920, AU200019804, and has filed patent applications US2002034820, CA2360762, CN1344314T, JP2002535984, IL144683D, PL350191, HU0200048 (international patent priority WO0046353 of 15.12.1999). The other authors declare that they have no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expression of mismatch repair enzymes in human sebaceous tumours. (PDF 8952 kb)

Supplementary Fig. 2

Groucho/TLE expression and interaction with LEF1. (PDF 11345 kb)

Supplementary Fig. 3

Expression of p53 and MMP7 in human SCC and sebaceous tumours. (PDF 20299 kb)

Supplementary Table 1

Panel of sebaceous tumours examined. (PDF 37 kb)

Supplementary Methods (PDF 79 kb)

Supplementary Note (PDF 28 kb)

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Takeda, H., Lyle, S., Lazar, A. et al. Human sebaceous tumors harbor inactivating mutations in LEF1. Nat Med 12, 395–397 (2006). https://doi.org/10.1038/nm1386

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