Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells
- University of Chicago, United States
- Université de Montréal, Canada
- Loyola University Chicago, United States
Abstract
Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend ERα cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated lasofoxifene derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.
Data availability
All protein crystal structures have been deposited in the PDB under accession codes: 6PSJ, 7KBS, 7UJC, 7UJ8, 7UJM, 7UJY, 7UJF, 7UJW, 7UJO, 7UJ7, 6V8T, and 6VPF.
Article and author information
Author details
Funding
Susan G. Komen (CCR19608597)
- Sean W Fanning
Ludwig Fund for Metastasis Research
- Geoffrey L Greene
Canadian Institutes of Health Research
- Sylvie C Mader
The funders had no role in the execution of this study.
Copyright
© 2022, Hosfield 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.
Metrics
-
- 2,307
- views
-
- 473
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells
eLife 11:e72512.
https://doi.org/10.7554/eLife.72512
Further reading
-
- Biochemistry and Chemical Biology
- Neuroscience
As the world population ages, new molecular targets in aging and Alzheimer’s disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. We found that rG4 immunostaining strongly increased in the hippocampus with both age and with AD severity. We further found that neurons with the accumulation of phospho-tau immunostaining contained rG4s, rG4 structure can drive tau aggregation, and rG4 staining density depended on APOE genotype in the human tissue examined. Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation is linked to proteostasis collapse. These morphological findings suggest that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Nature has inspired the design of improved inhibitors for cancer-causing proteins.
