title: Endoxifen's molecular mechanisms of action are concentration dependent and different than that of other anti-estrogens.
abstract: Endoxifen, a cytochrome P450 mediated tamoxifen metabolite, is being developed as a drug for the treatment of estrogen receptor (ER) positive breast cancer. Endoxifen is known to be a potent anti-estrogen and its mechanisms of action are still being elucidated. Here, we demonstrate that endoxifen-mediated recruitment of ERα to known target genes differs from that of 4-hydroxy-tamoxifen (4HT) and ICI-182,780 (ICI). Global gene expression profiling of MCF7 cells revealed substantial differences in the transcriptome following treatment with 4HT, endoxifen and ICI, both in the presence and absence of estrogen. Alterations in endoxifen concentrations also dramatically altered the gene expression profiles of MCF7 cells, even in the presence of clinically relevant concentrations of tamoxifen and its metabolites, 4HT and N-desmethyl-tamoxifen (NDT). Pathway analysis of differentially regulated genes revealed substantial differences related to endoxifen concentrations including significant induction of cell cycle arrest and markers of apoptosis following treatment with high, but not low, concentrations of endoxifen. Taken together, these data demonstrate that endoxifen's mechanism of action is different from that of 4HT and ICI and provide mechanistic insight into the potential importance of endoxifen in the suppression of breast cancer growth and progression.
authors: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA. hawse.john@mayo.edu
authors: John R
authors: JR
authors: Hawse
authors: Malayannan
authors: M
authors: Subramaniam
authors: Muzaffer
authors: M
authors: Cicek
authors: Xianglin
authors: X
authors: Wu
authors: Anne
authors: A
authors: Gingery
authors: Sarah B
authors: SB
authors: Grygo
authors: Zhifu
authors: Z
authors: Sun
authors: Kevin S
authors: KS
authors: Pitel
authors: Wilma L
authors: WL
authors: Lingle
authors: Matthew P
authors: MP
authors: Goetz
authors: James N
authors: JN
authors: Ingle
authors: Thomas C
authors: TC
authors: Spelsberg
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004965:Estrogen Antagonists / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D011485:Protein Binding; D015203:Reproducibility of Results; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen
references: Lancet. 2005 May 14-20;365(9472):1687-717
references: 15894097
references: Mol Endocrinol. 2008 Jul;22(7):1579-95
references: 18483178
references: J Pharmacol Exp Ther. 2006 Aug;318(2):503-12
references: 16690721
references: Cancer Res. 1984 Jan;44(1):112-9
references: 6537799
references: J Biol Chem. 1981 Jan 25;256(2):859-68
references: 7451477
references: J Natl Cancer Inst. 2003 Dec 3;95(23):1758-64
references: 14652237
references: Lancet. 1998 May 16;351(9114):1451-67
references: 9605801
references: J Pharmacol Exp Ther. 2004 Sep;310(3):1062-75
references: 15159443
references: Cancer Res. 2009 Mar 1;69(5):1722-7
references: 19244106
references: Cell. 2000 Dec 8;103(6):843-52
references: 11136970
references: Clin Pharmacol Ther. 2006 Jul;80(1):61-74
references: 16815318
references: Cancer Res. 1982 Jan;42(1):317-23
references: 7053859
references: Br J Clin Pharmacol. 2004 Dec;58(7):S744-7; discussion 748-50
references: 15595963
references: Clin Pharmacol Ther. 2011 May;89(5):718-25
references: 21430657
references: Breast Cancer Res Treat. 2004 May;85(2):151-9
references: 15111773
references: N Engl J Med. 1998 Nov 26;339(22):1609-18
references: 9828250
references: EMBO J. 2009 May 20;28(10):1418-28
references: 19339991
references: Proc Natl Acad Sci U S A. 1992 May 1;89(9):4037-41
references: 1570330
references: Bioinformatics. 2004 Nov 1;20(16):2778-86
references: 15166021
references: Cancer Res. 1986 Mar;46(3):1521-5
references: 3943109
references: Breast Cancer Res Treat. 1982;2(2):123-38
references: 6184101
references: Cancer Chemother Pharmacol. 2005 May;55(5):471-8
references: 15685451
references: Pharmacol Rev. 2001 Mar;53(1):25-71
references: 11171938