期刊
MOLECULAR PHARMACOLOGY
卷 98, 期 1, 页码 24-37出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.120.119776
关键词
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资金
- Department of Defense Breast Center of Excellence Program [W81XWH-06-1-0590]
- Susan G. Komen for the Cure Foundation [SAC100009]
- National Institutes of Health MD Anderson's Cancer Center Support Grant [CA016672]
- Cancer Prevention Research Institute of Texas (CPRIT)
- Dallas/Fort Worth Living Legend Chair of Cancer Research [1.1/2020]
- National Cancer Institute, NIH Informatics Technology for Cancer Research program [U24CA199461]
- Department of Defense BCRP Breakthrough Award [W81XWH-14-1-0360]
- Susan G. Komen Postdoctoral Fellowship [PDF14301382]
- Virginia and D.K. Ludwig Fund for Cancer Research
- Dan L. Duncan Comprehensive Cancer Center grant [NIH P30 CA125123]
- CPRIT Proteomics and Metabolomics Core Facility Award [RP170005]
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- Adrienne Helis Malvin Medical Research Foundation
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 molecular mechanism of estrogens at the estrogen receptor (ER) complex by different types of estrogens-planar [17 beta-estradiol (E-2)] 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 E-2 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 E-2-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 E-2. 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.
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