Biological Sciences Division
Published November 29, 2018 | Version v1
Journal article Open

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

Creators

  • 1. University of Chicago
  • 2. Dana-Farber Cancer Institute
  • 3. The Scripps Research Institute
  • 4. University of Illinois at Urbana-Champaign
  • 5. Texas A&M University
  • 6. PamGene International BV
  • 7. Memorial Sloan Kettering Cancer Center

Description

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

X-ray crystallographic data were deposited in the PDB under the accession code 4XI3.

The following data sets were generated:

Fanning SW Mayne CG Toy W Carlson K Green B Nowak J Walte R Panchamukhi S Tajkhorshid E Nettles KW Chandaralapaty S Katznellenbogen JA Greene GL (2015) Protein Data Bank ID 4XI3. Estrogen Receptor Alpha Ligand Binding Domain in Complex with Bazedoxifene. https://www.rcsb.org/structure/4xi3

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Additional details

Identifiers

DOI
10.7554/eLife.37161
Other
oai:uchicago.tind.io:10441

Funding

Susan G. Komen
PDF14301382
U.S. Department of Defense
Breakthrough Award
National Cancer Institute
CCSG P30 CA08748
National Institutes of Health
R01CA204999
National Institutes of Health
R35GM124952
National Science Foundation
CCF-1546278
Breast Cancer Research Foundation
BCRF-17-083
National Institutes of Health
R01CA220284
Virginia and D.K. Ludwig Fund for Cancer Research

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Ben May Department for Cancer Research