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Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis

Abstract

Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene, PAX2, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the PAX2 promoter.

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Figure 1: Genomic view of tamoxifen action.
Figure 2: Effect of EKLF, PKCα and PAX2 on the growth of EECs.
Figure 3: Effect of PAX2 on the growth of transplanted ECC-1 tumours in nude mice.
Figure 4: PAX2 as a downstream target of ERα.
Figure 5: Cancer-linked hypomethylation of the PAX2 promoter.

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Acknowledgements

We thank J. Green for editorial assistance. This work was supported by grants from the National Natural Science Foundation of China and from the ‘863 Program’ and the ‘973 Program’ of the Ministry of Science and Technology of China (to Y.S.).

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Correspondence to Yongfeng Shang.

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The microarray data are deposited in the Gene Expression Omnibus under accession number GSE3013. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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Wu, H., Chen, Y., Liang, J. et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438, 981–987 (2005). https://doi.org/10.1038/nature04225

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