title: The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells.
abstract: Tamoxifen has been the most important therapeutic agent for the treatment of estrogen receptor (ER)-positive breast cancer for the past three decades. Tamoxifen is extensively metabolized by cytochrome P450 enzymes, and recent in vivo studies have shown that women with genetically impaired cytochrome P450 2D6 have reduced production of endoxifen and a higher risk of breast cancer recurrence. Despite these observations, the contribution of endoxifen to the overall drug effectiveness of tamoxifen remains uncertain. Here, we provide novel evidence that endoxifen is a potent antiestrogen that functions in part by targeting ERalpha for degradation by the proteasome in breast cancer cells. Additionally, we show that endoxifen blocks ERalpha transcriptional activity and inhibits estrogen-induced breast cancer cell proliferation even in the presence of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxytamoxifen. All of the effects of endoxifen are concentration dependent and do not occur at concentrations observed in human CYP2D6 poor metabolizers. These results support the theory that endoxifen is the primary metabolite responsible for the overall effectiveness of tamoxifen in the treatment of ER-positive breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Xianglin
authors.initials: X
authors.lastname: Wu
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Spelsberg
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D020218:Response Elements / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6