The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells-Reference-Cited by-同舟云学术

The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells

Published:2018-11-29 Issue: Volume:7 Page:
ISSN:2050-084X
Container-title:eLife
language:en
Short-container-title:

Author:

Fanning Sean W¹^ORCID,Jeselsohn Rinath²³,Dharmarajan Venkatasubramanian⁴,Mayne Christopher G⁵^ORCID,Karimi Mostafa⁶,Buchwalter Gilles²,Houtman René⁷,Toy Weiyi⁸,Fowler Colin E¹^ORCID,Han Ross¹,Lainé Muriel¹,Carlson Kathryn E⁹,Martin Teresa A⁹,Nowak Jason³,Nwachukwu Jerome C¹⁰^ORCID,Hosfield David J¹,Chandarlapaty Sarat⁸^ORCID,Tajkhorshid Emad⁵^ORCID,Nettles Kendall W⁴,Griffin Patrick R⁴^ORCID,Shen Yang⁶^ORCID,Katzenellenbogen John A⁹^ORCID,Brown Myles²³^ORCID,Greene Geoffrey L¹^ORCID

Affiliation:

1. Ben May Department for Cancer Research, University of Chicago, Chicago, United States

2. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States

3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States

4. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

5. Department of Biochemistry, College of Medicine, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States

6. Department of Electrical and Computer Engineering, TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering, Texas A&M University, Texas, United States

7. PamGene International BV, ‘s-Hertogenbosch, The Netherlands

8. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States

9. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, United States

10. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States

Abstract

Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.

Funder

Susan G. Komen

U.S. Department of Defense

National Cancer Institute

National Institutes of Health

National Science Foundation

Breast Cancer Research Foundation

Virginia and D.K. Ludwig Fund for Cancer Research

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience