RT Journal Article
SR Electronic
T1 The Structure-Function Relationship of Angular Estrogens and Estrogen Receptor Alpha to Initiate Estrogen-Induced Apoptosis in Breast Cancer Cells.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.120.119776
DO 10.1124/mol.120.119776
A1 Philipp Y. Maximov
A1 Balkees Abderrahman
A1 Yousef M. Hawsawi
A1 Yue Chen
A1 Charles E. Foulds
A1 Antrix Jain
A1 Anna Malovannaya
A1 Ping Fan
A1 Ramona F. Curpan
A1 Ross Han
A1 Sean W. Fanning
A1 Bradley M. Broom
A1 Daniela M. Quintana Rincon
A1 Jeffery A. Greenland
A1 Geoffrey L. Greene
A1 V. Craig Jordan
YR 2020
UL http://molpharm.aspetjournals.org/content/early/2020/05/03/mol.120.119776.abstract
AB High dose synthetic estrogen therapy was the standard treatment for advanced breast cancer for three decades until the discovery of tamoxifen. A range of substituted triphenylethylene synthetic estrogens and diethylstilbestrol (DES) 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, 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 (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 sidechain 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 would contains an antiestrogenic sidechain 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 Estrogen-induced apoptosis is a novel mechanism of breast cancer cell death that has clinical significance. In this paper we investigate the role of the structure-function relationship of a panel of synthetic TPE derivatives related to compounds that have been tested decades earlier in high dose estrogen therapy of advanced breast cancer. 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 coregualtors and subsequently different apoptotic effects on the antiestrogen-resistant breast cancer cells.