TY - JOUR
T1 - Pharmacology and molecular mechanisms of clinically relevant estrogen estetrol and estrogen mimic BMI-135 for the treatment of endocrine-resistant breast cancer
AU - Abderrahman, Balkees
AU - Maximov, Philipp Y.
AU - Curpan, Ramona F.
AU - Hanspal, Jay S.
AU - Fan, Ping
AU - Xiong, Rui
AU - Tonetti, Debra A.
AU - Thatcher, Gregory R.J.
AU - Jordan, V. Craig
N1 - Funding Information:
This work was supported by National Institutes of Health National Cancer Institute MD Anderson Cancer Center Support Grant [Grant CA016672] to Peter Pisters; the George and Barbara Bush Foundation for Innovative Cancer Research (V.C.J.); the Cancer Prevention Research Institute of Texas (CPRIT) for the Science and Technology Acquisition and Retention (STARs) and STARs Plus Awards (V.C.J.); the Dallas/Fort Worth Living Legend Fellowship of Cancer Research (B.A.); and the Coriolan Dragulescu Institute of Chemistry of the Romanian Academy [Project no. 1.1/2020] (R.F.C.). Authors disclose no conflicts of interest. https://doi.org/10.1124/molpharm.120.000054. s This article has supplemental material available at molpharm. aspetjournals.org.
Publisher Copyright:
Copyright © 2020 The Author(s).
PY - 2020/10
Y1 - 2020/10
N2 - Long-term estrogen deprivation (LTED) with tamoxifen (TAM) or aromatase inhibitors leads to endocrine-resistance, whereby physiologic levels of estrogen kill breast cancer (BC). Estrogen therapy is effective in treating patients with advanced BC after resistance to TAM and aromatase inhibitors develops. This therapeutic effect is attributed to estrogen-induced apoptosis via the estrogen receptor (ER). Estrogen therapy can have unpleasant gynecologic and nongynecologic adverse events. Here, we study estetrol (E4) and a model Selective Human ER Partial Agonist (ShERPA) BMI-135. Estetrol and ShERPA TTC- 352 are being evaluated in clinical trials. These agents are proposed as safer estrogenic candidates compared with 17β-estradiol (E2) for the treatment of endocrine-resistant BC. Cell viability assays, real-time polymerase chain reaction, luciferase reporter assays, chromatin immunoprecipitation, docking and molecular dynamics simulations, human unfolded protein response (UPR) RT2 PCR profiler arrays, live cell microscopic imaging and analysis, and annexin V staining assays were conducted. Our work was done in eight biologically different human BC cell lines and one human endometrial cancer cell line, and results were compared with full agonists estrone, E2, and estriol, a benchmark partial agonist triphenylethylene bisphenol (BPTPE), and antagonists 4-hydroxytamoxifen and endoxifen. Our study shows the pharmacology of E4 and BMI- 135 as less-potent full-estrogen agonists as well as their molecular mechanisms of tumor regression in LTED BC through triggering a rapid UPR and apoptosis. Our work concludes that the use of a full agonist to treat BC is potentially superior to a partial agonist given BPTPE's delayed induction of UPR and apoptosis, with a higher probability of tumor clonal evolution and resistance.
AB - Long-term estrogen deprivation (LTED) with tamoxifen (TAM) or aromatase inhibitors leads to endocrine-resistance, whereby physiologic levels of estrogen kill breast cancer (BC). Estrogen therapy is effective in treating patients with advanced BC after resistance to TAM and aromatase inhibitors develops. This therapeutic effect is attributed to estrogen-induced apoptosis via the estrogen receptor (ER). Estrogen therapy can have unpleasant gynecologic and nongynecologic adverse events. Here, we study estetrol (E4) and a model Selective Human ER Partial Agonist (ShERPA) BMI-135. Estetrol and ShERPA TTC- 352 are being evaluated in clinical trials. These agents are proposed as safer estrogenic candidates compared with 17β-estradiol (E2) for the treatment of endocrine-resistant BC. Cell viability assays, real-time polymerase chain reaction, luciferase reporter assays, chromatin immunoprecipitation, docking and molecular dynamics simulations, human unfolded protein response (UPR) RT2 PCR profiler arrays, live cell microscopic imaging and analysis, and annexin V staining assays were conducted. Our work was done in eight biologically different human BC cell lines and one human endometrial cancer cell line, and results were compared with full agonists estrone, E2, and estriol, a benchmark partial agonist triphenylethylene bisphenol (BPTPE), and antagonists 4-hydroxytamoxifen and endoxifen. Our study shows the pharmacology of E4 and BMI- 135 as less-potent full-estrogen agonists as well as their molecular mechanisms of tumor regression in LTED BC through triggering a rapid UPR and apoptosis. Our work concludes that the use of a full agonist to treat BC is potentially superior to a partial agonist given BPTPE's delayed induction of UPR and apoptosis, with a higher probability of tumor clonal evolution and resistance.
UR - http://www.scopus.com/inward/record.url?scp=85091125887&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091125887&partnerID=8YFLogxK
U2 - 10.1124/MOLPHARM.120.000054
DO - 10.1124/MOLPHARM.120.000054
M3 - Article
C2 - 32788222
AN - SCOPUS:85091125887
VL - 69
SP - 364
EP - 381
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 5
ER -