cancer cells and as a partial agonist in bone and the cardiovascular system. Members of the cytochrome P 450 (CYP) phase I and of phase II biotransformation pathways are responsible for the metabolism of the drug in human liver microsomes (HLM) and rat hepatic cytosol. TAM is extensively metabolized and both primary and secondary metabolites have higher potencies than the parent compound.  Primary metabolites include alpha-OH-TAM and DMT or 4-OH-TAM of which alpha-OH-TAM can form toxic DNA adducts; DMT and 4-OH-TAM are further metabolized to the secondary metabolite endoxifen. Tamoxifen and its metabolites bind the estrogen receptors Esr1 and 2 (ER), albeit with somewhat different affinities. They block binding of estradiol to the receptors, prevent the conformational changes required for binding of coactivators and lead to preferential recruitment of corepressors such as Ncor1 and others. The suppressed transcriptional activity of the receptors results in suppressed tumor growth as genes regulated by estrogen are involved in proliferation, angiogenesis, anti-apoptosis, among others. However, the levels of ER coregulators, the phosphorylation of both receptors and coregulators and associated functional impacts, the non-genomic function of membrane-tethered ER receptors and cross-talk to growth factors, including over-expression of certain growth factor receptors such as Erbb2/Her2, can all contribute to tamoxifen resistance and promote survival of the breast cancer cell. For instance, Ncoa3 coactivator also known as Aib1 or Src3, is overexpressed and gene amplified in 64-65% and 5-10% of breast cancers, respectively.  It is also to be noted that TAM can activate the membrane-tethered ERs in a manner analogous to estrogen ligands, thus  accounting for its agonistic effects, including drug resistance. Endoxifen - the major metabolite responsible for the action of tamoxifen in vivo, appears to have differential effects on the two receptors. It stabilizes the beta receptor, promotes receptor heterodimerization and has a more inhibitory effect on the expression of target genes. On the other hand, endoxifen targets the alpha estrogen receptor for proteasomal degradation in breast cancer cells. Polymorphisms in several CYP phase I and UGT phase II enzymes of TAM metabolism impact on the relative abundance and availability of metabolites and subsequently on their effect on estrogen-induced breast cancer cell proliferation. To see the ontology report for annotations, GViewer and download, click here
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