Publication Date
1-1-2021
Journal
Molecular Cancer Therapeutics
DOI
10.1158/1535-7163.MCT-20-0563
PMID
33177154
PMCID
PMC7790886
PubMedCentral® Posted Date
7-1-2021
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Apoptosis, Benzothiazoles, Biomarkers, Tumor, Breast Neoplasms, Cell Survival, DNA, Neoplasm, Drug Resistance, Neoplasm, Endoribonucleases, Estrogens, Female, Fluorescence, Gene Expression Regulation, Neoplastic, Hormones, Humans, Ligands, MCF-7 Cells, Models, Biological, Molecular Dynamics Simulation, Protein Binding, Protein Domains, Protein Serine-Threonine Kinases, Receptors, Estrogen, Thermodynamics, Transcription, Genetic, Unfolded Protein Response, X-Box Binding Protein 1, Selective Human Estrogen Receptor Partial Agonists (ShERPAs), estetrol (E4), estrogen receptor (ER), coactivators, unfolded protein response, apoptosis
Abstract
Patients with long-term estrogen-deprived breast cancer (BC), after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen’s anti-tumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecological and non-gynecological adverse events thus the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEMs) BMI-135 and TTC-352, and the naturally-occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared to 17β-estradiol (E2), for the treatment of endocrine-resistant BC. TTC-352 and E4 are being evaluated in BC clinical trials. Cell viability assays, real-time polymerase chain reaction, immunoblotting, ERE DNA pull downs, Mass spectrometry, X-ray crystallography, docking and molecular dynamic simulations, live cell imaging, and annexin V staining were conducted in 11 biologically-different BC models. Results were compared with the potent full agonist E2, less potent full agonist E4, the benchmark partial agonist triphenylethylene bisphenol (BPTPE), and antagonists 4-hydroxytamoxifen and endoxifen. We report ERα’s regulation and coregulators’ binding profiles with SEMs and E4. We describe TTC-352’s pharmacology as a weak full agonist and anti-tumor molecular mechanisms. This study highlights TTC-352’s benzothiophene scaffold that yields an H-bond with Glu353, which allows Asp351-to-helix 12 (H12) interaction; sealing ERα’s ligand binding domain, recruiting E2-enriched coactivators, and triggering rapid ERα-induced unfolded protein response (UPR) and apoptosis, as the basis of its anti-cancer properties. BPTPE’s phenolic OH yields an H-Bond with Thr347, which disrupts Asp351-to-H12 interaction; delaying UPR and apoptosis, and increasing clonal evolution risk.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biology Commons, Diseases Commons, Genetic Phenomena Commons, Obstetrics and Gynecology Commons, Oncology Commons
