Tamoxifen competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal.
Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited.
Tamoxifen binds to estrogen receptor (ER) which in turn interacts with DNA. The ER/tamoxifen complex recruits other proteins known as co-repressors to stop genes being switched on by estrogen. Some of these proteins include NCoR and SMRT. Tamoxifen function can be regulated by a number of different variables including growth factors. Tamoxifen needs to block growth factor proteins such as ErbB2/HER2 because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers. Tamoxifen seems to require a protein PAX2 for its full anticancer effect. In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/estrogen receptor complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.
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Last Updated: Feb 1, 2011