Antagonistic and agonistic effects of tamoxifen: significance in human cancer.

Tamoxifen is a substituted triphenylethylene antiestrogen used in the adjuvant therapy and chemoprevention of breast cancer. The antiestrogenic activity of the compound has been attributed to its metabolism to an active 4-hydroxy derivative and the avid binding of the active metabolite to the estrogen receptor. Receptor binding of the antiestrogen alters the transcriptional activity normally attributed to the estradiol-bound estrogen receptor. Tamoxifen is both an antagonist and an agonist of the estrogen receptor. However, a molecular explanation exists for this apparent paradox. The dual action is a function of the estrogen receptor complex present in a particular cell or tissue. If a cell type requires activating factors 1 and 2 of the estrogen receptor to be functioning concurrently, tamoxifen is antagonistic. However, if a cell or tissue requires only activating factor 1 to interact with transcription factors at the promoter, tamoxifen is agonistic. The implication is that the investigators must understand the fundamental biology of the estrogen receptor complex in a tissue context before one can predict tissue activity of tamoxifen.