Tamoxifen and Endometrial Cancer: A Janus-Headed Drug

Tamoxifen is a selective estrogen receptor modulator used for the treatment and prevention of estrogen receptor (ER)—positive breast cancer. However, tamoxifen increases the risk of endometrial cancer (EC) by about 2–7 fold, and more aggressive types of EC with poor prognoses are observed in tamoxifen users. On the other hand, tamoxifen is an efficacious treatment for advanced or recurrent EC with low toxicity. The differential agonistic or antagonistic effects of tamoxifen on ERα are explained by the tissue-specific expression profiles of co-activators and co-repressors of the receptor. The estrogen-agonistic effect of tamoxifen in endometrial cancers can also be explained by the expression of G-protein coupled estrogen receptor 1 (GPER-1), a membrane-bound estrogen receptor for which tamoxifen and other “antiestrogens” are pure agonists.