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.
Gallo
M A
MA
University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08855, USA.
Kaufman
D
D
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000494:pharmacology*; D016889:Endometrial Neoplasms / Q000139:chemically induced; D004717:Endometrium / Q000187:drug effects; D005260:Female; D006801:Humans; D011960:Receptors, Estrogen / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013629:Tamoxifen