Abstract
High-dose synthetic estrogen therapy was the standard treatment of advanced breast cancer for three decades until the discovery of tamoxifen. A range of substituted triphenylethylene synthetic estrogens and diethylstilbestrol were used. It is now known that low doses of estrogens can cause apoptosis in long-term estrogen deprived (LTED) breast cancer cells resistant to antiestrogens. This action of estrogen can explain the reduced breast cancer incidence in postmenopausal women over 60 who are taking conjugated equine estrogens and the beneficial effect of low-dose estrogen treatment of patients with acquired aromatase inhibitor resistance in clinical trials. To decipher the molecular mechanism of estrogens at the estrogen receptor (ER) complex by different types of estrogens—planar [17β-estradiol (E2)] and angular triphenylethylene (TPE) derivatives—we have synthesized a small series of compounds with either no substitutions on the TPE phenyl ring containing the antiestrogenic side chain of endoxifen or a free hydroxyl. In the first week of treatment with E2 the LTED cells undergo apoptosis completely. By contrast, the test TPE derivatives act as antiestrogens with a free para-hydroxyl on the phenyl ring that contains an antiestrogenic side chain in endoxifen. This inhibits early E2-induced apoptosis if a free hydroxyl is present. No substitution at the site occupied by the antiestrogenic side chain of endoxifen results in early apoptosis similar to planar E2. The TPE compounds recruit coregulators to the ER differentially and predictably, leading to delayed apoptosis in these cells.
SIGNIFICANCE STATEMENT In this paper we investigate the role of the structure-function relationship of a panel of synthetic triphenylethylene (TPE) derivatives and a novel mechanism of estrogen-induced cell death in breast cancer, which is now clinically relevant. Our study indicates that these TPE derivatives, depending on the positioning of the hydroxyl groups, induce various conformations of the estrogen receptor’s ligand-binding domain, which in turn produces differential recruitment of coregulators and subsequently different apoptotic effects on the antiestrogen-resistant breast cancer cells.
Footnotes
- Received February 10, 2020.
- Accepted April 16, 2020.
This work was supported by the Department of Defense Breast Center of Excellence Program [W81XWH-06-1-0590]; the Susan G. Komen for the Cure Foundation [SAC100009]; the National Institutes of Health MD Anderson’s Cancer Center Support Grant, [CA016672 to P.W. Pisters]; and Cancer Prevention Research Institute of Texas (CPRIT) for the STARs and STARs plus Awards (to V.C.J.). V.C.J. thanks the George and Barbara Bush Foundation for Innovative Cancer Research and the benefactors of the Dallas/Fort Worth Living Legend Chair of Cancer Research for their generous support; the “Coriolan Dragulescu” Institute of Chemistry [Project no. 1.1/2020]; a grant from the National Cancer Institute, NIH Informatics Technology for Cancer Research program [U24CA199461]; the Department of Defense BCRP Breakthrough Award [W81XWH-14-1-0360]; the Susan G. Komen Postdoctoral Fellowship [PDF14301382] and the Virginia and D.K. Ludwig Fund for Cancer Research. The Baylor College of Medicine Mass Spectrometry Proteomics Core is supported by the Dan L. Duncan Comprehensive Cancer Center grant [NIH P30 CA125123] and CPRIT Proteomics and Metabolomics Core Facility Award [RP170005]. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]. C.E.F. and Y.C. were supported by the Adrienne Helis Malvin Medical Research Foundation through its direct engagement in the continuous active conduct of medical research in conjunction with Baylor College of Medicine. C.E.F. also discloses an equity position in Coactigon, Inc.
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- Copyright © 2020 The Author(s)
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