Antigen presentation: A marked loss

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Activation of paired box gene 2 (PAX2) in endometrial carcinomas by estrogen or tamoxifen could explain the increased incidence of endometrial cancer associated with tamoxifen use.

Tamoxifen is used to treat breast cancer, but its use is associated with an increased incidence of endometrial cancer. Wu et al. have now identified the oestrogenic pathway through which tamoxifen achieves this carcinogenic effect.

Given that both tamoxifen and oestrogen bind to oestrogen receptors to mediate their effects, the authors used microarrays to compare their effects on gene expression in endometrioid carcinoma samples. There was an overlap in the sets of genes that were regulated by the two molecules, but two-thirds of each set was unique. This implies that oestrogen and tamoxifen operate through distinct pathways.

The authors then looked at the genes that were regulated by both molecules and found that one upregulated gene, paired box gene 2 (PAX2), significantly increased proliferation when overexpressed in endometrioid tumours. In addition, silencing of PAX2 reduced proliferation in tumours that had been stimulated by oestrogen or tamoxifen.

These results imply that PAX2 mediates tamoxifen-stimulated carcinogenesis, so the authors looked at the expression pattern of PAX2 in carcinomas. They found that expression of PAX2 correlates with that of oestrogen receptor- alpha (ER) and that ER alpha binds to the upstream regulatory region of PAX2.

In addition, the authors found that the PAX2 promoter was hypomethylated in carcinoma samples, whereas it is hypermethylated in normal endometrial tissue. They suggest that this loss of methylation is the reason why tamoxifen-bound ER alpha can activate PAX2 expression. How this hypomethylation occurs requires further study, but the identification of the role of PAX2 offers a potential new drug target.

Patrick Goymer

References

Wu, H. et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438, 981–987 (2005) | Article | PubMed |
Robson, E. J. D. et al. A PANorama of PAX genes in cancer and development. Nature Rev. Cancer 6, 52–62 (2006) | Article |