The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells
- University of Chicago, United States
- Dana-Farber Cancer Institute, United States
- The Scripps Research Institute, United States
- University of Illinois at Urbana-Champaign, United States
- Texas A&M University, United States
- PamGene International, Netherlands
- Memorial Sloan Kettering Cancer Center, 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.
Data availability
X-ray crystallographic data were deposited in the PDB under the accession code 4XI3.
Article and author information
Author details
Christopher G Mayne
Jerome C Nwachukwu
Sarat Chandarlapaty
Funding
Susan G. Komen (PDF14301382)
- Sean W Fanning
- Geoffrey L Greene
National Cancer Institute (CCSG P30 CA08748)
- Sarat Chandarlapaty
Breast Cancer Research Foundation (BCRF-17-083)
- John A Katzenellenbogen
National Institutes of Health (R01CA204999)
- Sarat Chandarlapaty
U.S. Department of Defense (Breakthrough Award W81XWH-14-1-0360)
- Sean W Fanning
- Weiyi Toy
- Colin E Fowler
- Sarat Chandarlapaty
- Geoffrey L Greene
National Institutes of Health (R35GM124952)
- Yang Shen
National Science Foundation (CCF-1546278)
- Yang Shen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Fanning et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells
eLife 7:e37161.
https://doi.org/10.7554/eLife.37161
Further reading
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