Endoxifen, 4-hydroxytamoxifen and an estrogenic derivative modulate estrogen receptor complex mediated apoptosis in breast cancer

Philipp Y. Maximov, Balkees Abderrahman, Sean W. Fanning, Surojeet Sengupta, Ping Fan, Ramona F. Curpan, Daniela Maria Quintana Rincon, Jeffery A. Greenland, Shyamala S. Rajan, Geoffrey L. Greene, V. Craig Jordan

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


Estrogen therapy was used to treat advanced breast cancer in postmenopausal women for decades until the introduction of tamoxifen. Resistance to long-term estrogen deprivation (LTED) with tamoxifen and aromatase inhibitors used as a treatment of breast cancer inevitably occurs, but unexpectedly low-dose estrogen can cause regression of breast cancer and increase disease-free survival in some patients. This therapeutic effect is attributed to estrogen-induced apoptosis in LTED breast cancer. Here, we describe modulation of the estrogen receptor (ER) liganded with antiestrogens (endoxifen and 4-hydroxytamoxifen) and an estrogenic triphenylethylene (TPE), ethoxytriphenylethylene (EtOXTPE), on estrogen-induced apoptosis in LTED breast cancer cells. Our results show that the angular TPE estrogen (EtOXTPE) is able to induce the ER-mediated apoptosis only at a later time compared with planar estradiol in these cells. Using real-time polymerase chain reaction, chromatin immunoprecipitation, western blotting, molecular modeling, and X-ray crystallography techniques, we report novel conformations of the ER complex with an angular estrogen EtOXTPE and endoxifen. We propose that alteration of the conformation of the ER complexes, with changes in coactivator binding, governs estrogen-induced apoptosis through the protein kinase regulated by RNA-like endoplasmic reticulum kinase sensor system to trigger an unfolded protein response.

Original languageEnglish (US)
Pages (from-to)812-822
Number of pages11
JournalMolecular Pharmacology
Issue number2
StatePublished - Aug 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Department of Defense Breast Center of Excellence Program [Award W81XWH-06-1-0590]; the Susan G. Komen for the Cure Foundation [Award SAC100009]; the National Institutes of Health Lombardi Comprehensive Cancer Center [Grant P30 CA051008]; the National Institutes of Health MD Anderson’s Cancer Center [Grant CA016672]; the Institute of Chemistry Timisoara of the Romanian Academy [Project 1.1/2015]; the Romanian National Authority for Scientific Research and Innovation, CNCS–UEFISCDI [Project PN-II-RU-TE-2014-4-0422]; the Department of Defense BCRP [Breakthrough Award W81XWH-14-1-0360]; the Susan G Komen Postdoctoral Fellowship [Grant PDF14301382]; and the Virginia and D. K. Ludwig Fund for Cancer Research.

Publisher Copyright:
Copyright © 2018 by The Author(s)


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