Actions of tamoxifen in the uterus and its molecular effectors in endometrial carcinogenesis.

The molecular explanation for tamoxifen serving as a breast cancer treatment but displaying partial estrogenic in the uterus is not known. Previously, we reported that differential promoter context and cofactor recruitment contribute to the tissue specificity of tamoxifen. Here, we investigated the genomic basis for the partial oestrogenic activity of tamoxifen in the endometrium. We showed that tamoxifen not only affects the rate of transcription of oestrogen target genes but also targets a unique set of genes. Since oestrogen and tamoxifen are both able to bind to oestrogen receptors (ERs) and because both promote endometrial carcinogenesis, we hypothesized that the molecular effectors for ERs in endometrial carcinogenesis most likely reside in genes that are commonly targeted by oestrogen and tamoxifen. Among those target genes, we identified a paired-box gene PAX2 that is critically involved in cell proliferation and carcinogenesis in the endometrium. Our experiments also demonstrated that PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and this activation is associated with cancer-linked hypomethylation of the PAX2 promoter.

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Wu H, Chen Y, Liang J, Shi B, Wu G, Zhang Y, Wang D, Li R, Yi X, Zhang H, Sun L, Shang Y