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

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. The tamoxifen paradox Why tamoxifen serves as a treatment for breast cancer but increases the incidence of endometrial cancer is of great importance both scientifically and practically. Analysis of targets common to both tamoxifen and oestrogen points to the PAX2 transcription factor as a key to the phenomenon. PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium. The identification of PAX2 as mediator of the carcinogenic activity of both oestrogen and tamoxifen in the uterus may provide useful information for the design of safer drugs for the treatment of breast cancer and endometrial cancer.