Endoxifen's Molecular Mechanisms of Action Are Concentration Dependent and Different than That of Other Anti-Estrogens

John R Hawse, Malayannan Subramaniam, Muzaffer Cicek, Xianglin Wu, Anne Gingery, Sarah B. Grygo, Zhifu Sun, Kevin S. Pitel, Wilma L. Lingle, Matthew Philip Goetz, James N. Ingle, Thomas C. Spelsberg

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere54613
JournalPLoS One
Volume8
Issue number1
DOIs
StatePublished - Jan 28 2013

Fingerprint

tamoxifen
estrogens
mechanism of action
Estrogens
Tamoxifen
breast neoplasms
MCF-7 Cells
Metabolites
Transcriptome
Gene expression
Estrogen Receptors
metabolites
gene expression
Genes
Breast Neoplasms
4-hydroxy-N-desmethyltamoxifen
cytochrome P-450
transcriptome
drug therapy
Gene Expression Profiling

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Endoxifen's Molecular Mechanisms of Action Are Concentration Dependent and Different than That of Other Anti-Estrogens. / Hawse, John R; Subramaniam, Malayannan; Cicek, Muzaffer; Wu, Xianglin; Gingery, Anne; Grygo, Sarah B.; Sun, Zhifu; Pitel, Kevin S.; Lingle, Wilma L.; Goetz, Matthew Philip; Ingle, James N.; Spelsberg, Thomas C.

In: PLoS One, Vol. 8, No. 1, e54613, 28.01.2013.

Research output: Contribution to journalArticle

Hawse, John R ; Subramaniam, Malayannan ; Cicek, Muzaffer ; Wu, Xianglin ; Gingery, Anne ; Grygo, Sarah B. ; Sun, Zhifu ; Pitel, Kevin S. ; Lingle, Wilma L. ; Goetz, Matthew Philip ; Ingle, James N. ; Spelsberg, Thomas C. / Endoxifen's Molecular Mechanisms of Action Are Concentration Dependent and Different than That of Other Anti-Estrogens. In: PLoS One. 2013 ; Vol. 8, No. 1.
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