2. Academic Validation
  3. Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer

Rapid Induction of the Unfolded Protein Response and Apoptosis by Estrogen Mimic TTC-352 for the Treatment of Endocrine-Resistant Breast Cancer

  • Mol Cancer Ther. 2021 Jan;20(1):11-25. doi: 10.1158/1535-7163.MCT-20-0563.
Balkees Abderrahman 1,  Philipp Y Maximov 1,  Ramona F Curpan 2,  Sean W Fanning 3,  Jay S Hanspal 1,  Ping Fan 1,  Charles E Foulds 4,  Yue Chen 5,  Anna Malovannaya 6,  Antrix Jain 7,  Rui Xiong 8,  Geoffrey L Greene 3,  Debra A Tonetti 8,  Gregory R J Thatcher 8,  V Craig Jordan 9
Affiliations

Affiliations

  • 1 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2 Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania.
  • 3 Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
  • 4 Center for Precision Environmental Health and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
  • 5 Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana.
  • 6 Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, Texas.
  • 7 Mass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, Texas.
  • 8 Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
  • 9 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. VCJordan@mdanderson.org.
PMID: 33177154 DOI: 10.1158/1535-7163.MCT-20-0563
Abstract

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 17β-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 ERα's regulation and coregulators' binding profiles with SEMs and E4 We describe TTC-352's pharmacology as a weak full agonist and antitumor 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 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.

Figures
Products