TY - JOUR
T1 - Rapid induction of the unfolded protein response and apoptosis by estrogen mimic ttc-352 for the treatment of endocrine-resistant breast cancer
AU - Abderrahman, Balkees
AU - Maximov, Philipp Y.
AU - Curpan, Ramona F.
AU - Fanning, Sean W.
AU - Hanspal, Jay S.
AU - Fan, Ping
AU - Foulds, Charles E.
AU - Chen, Yue
AU - Malovannaya, Anna
AU - Jain, Antrix
AU - Xiong, Rui
AU - Greene, Geoffrey L.
AU - Tonetti, Debra A.
AU - Thatcher, Gregory R.J.
AU - Jordan, V. Craig
N1 - Funding Information:
(B. Abderrahman); the Coriolan Dragulescu Institute of Chemistry of the Romanian Academy (R.F. Curpan, Project no. 1.1/2020); the Adrienne Helis Malvin Medical Research Foundation through direct engagement with the continuous active conduct of medical research in conjunction with BCM (C.E. Foulds and Y. Chen); the Baylor College of Medicine Mass Spectrometry Proteomics Core supported by the Dan L. Duncan Comprehensive Cancer Center grant (A. Malovannaya, NIH P30 CA125123) and CPRIT Proteomics and Metabolomics Core Facility Award (A. Malovannaya, RP170005); and the Argonne National Laboratory, Structural Biology Center (SBC), at the Advanced Photon Source operated by UChicago Argonne, LLC, for the U.S. Department of Energy, and
Funding Information:
We thank Dr. Robert Clarke for providing the LCC breast cancer cell line series. B. Abderrahman holds a dual position: the Dallas/Ft. Worth Living Legend Fellow of Cancer Research at the Department of Breast Medical Oncology, the University of Texas MD Anderson Cancer Center (TX, USA), and a split-site PhD trainee under Model C “Applicants of Very High Quality” at the Faculty of Biological Sciences, the University of Leeds (West Yorkshire, UK). This work was supported by the National Institutes of Health MD Anderson Cancer Center Support Grant (P.W. Pisters, CA016672); the George and Barbara Bush Foundation for Innovative Cancer Research (V.C. Jordan); the Cancer Prevention Research Institute of Texas (CPRIT) for the STARs and STARs Plus Awards (V.C. Jordan); the Dallas/Ft. Worth Living Legend Fellowship of Cancer Research
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Patients with long-term estrogen-deprived breast cancer, after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen’s antitumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecologic and nongynecologic adverse events; thus, the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEM) BMI-135 and TTC-352, and the naturally occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared with 17b-estradiol (E2), for the treatment of endocrine-resistant breast cancer. TTC-352 and E4 are being evaluated in breast cancer clinical trials. Cell viability assays, real-time PCR, immunoblotting, ERE DNA pulldowns, mass spectrometry, X-ray crystallography, docking and molecular dynamic simulations, live cell imaging, and Annexin V staining were conducted in 11 biologically different breast cancer 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 ERa’s regulation and coregulators’ binding profiles with SEMs and E4. We describe TTC-3520s pharmacology as a weak full agonist and antitumor molecular mechanisms. This study highlights TTC-3520s benzothiophene scaffold that yields an H-bond with Glu353, which allows Asp351-to-helix 12 (H12) interaction, sealing ERa’s ligand-binding domain, recruiting E2-enriched coactivators, and triggering rapid ERa-induced unfolded protein response (UPR) and apoptosis, as the basis of its anticancer 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.
AB - Patients with long-term estrogen-deprived breast cancer, after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen’s antitumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecologic and nongynecologic adverse events; thus, the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEM) BMI-135 and TTC-352, and the naturally occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared with 17b-estradiol (E2), for the treatment of endocrine-resistant breast cancer. TTC-352 and E4 are being evaluated in breast cancer clinical trials. Cell viability assays, real-time PCR, immunoblotting, ERE DNA pulldowns, mass spectrometry, X-ray crystallography, docking and molecular dynamic simulations, live cell imaging, and Annexin V staining were conducted in 11 biologically different breast cancer 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 ERa’s regulation and coregulators’ binding profiles with SEMs and E4. We describe TTC-3520s pharmacology as a weak full agonist and antitumor molecular mechanisms. This study highlights TTC-3520s benzothiophene scaffold that yields an H-bond with Glu353, which allows Asp351-to-helix 12 (H12) interaction, sealing ERa’s ligand-binding domain, recruiting E2-enriched coactivators, and triggering rapid ERa-induced unfolded protein response (UPR) and apoptosis, as the basis of its anticancer 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.
UR - http://www.scopus.com/inward/record.url?scp=85100449687&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100449687&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-20-0563
DO - 10.1158/1535-7163.MCT-20-0563
M3 - Article
C2 - 33177154
AN - SCOPUS:85100449687
SN - 1535-7163
VL - 20
SP - 11
EP - 25
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 1
ER -