Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells
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 estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagon...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/72512 |
| _version_ | 1797998460358623232 |
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| author | David J Hosfield Sandra Weber Nan-Sheng Li Madline Sauvage Carstyn F Joiner Govinda R Hancock Emily A Sullivan Estelle Ndukwe Ross Han Sydney Cush Muriel Lainé Sylvie C Mader Geoffrey L Greene Sean W Fanning |
| author_facet | David J Hosfield Sandra Weber Nan-Sheng Li Madline Sauvage Carstyn F Joiner Govinda R Hancock Emily A Sullivan Estelle Ndukwe Ross Han Sydney Cush Muriel Lainé Sylvie C Mader Geoffrey L Greene Sean W Fanning |
| author_sort | David J Hosfield |
| collection | DOAJ |
| description | 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 estrogen receptor alpha (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 (Laso) 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 Laso 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. |
| first_indexed | 2024-04-11T10:49:04Z |
| format | Article |
| id | doaj.art-a9802c2206974ca0b24d086125724f5f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:49:04Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a9802c2206974ca0b24d086125724f5f2022-12-22T04:28:58ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.72512Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cellsDavid J Hosfield0Sandra Weber1Nan-Sheng Li2Madline Sauvage3Carstyn F Joiner4Govinda R Hancock5Emily A Sullivan6Estelle Ndukwe7Ross Han8Sydney Cush9Muriel Lainé10Sylvie C Mader11Geoffrey L Greene12https://orcid.org/0000-0001-6894-8728Sean W Fanning13https://orcid.org/0000-0002-9428-0060Ben May Department for Cancer Research, University of Chicago, Chicago, United StatesInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, CanadaBen May Department for Cancer Research, University of Chicago, Chicago, United StatesInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, CanadaDepartment of Cancer Biology, Loyola University Chicago, Maywood, United StatesDepartment of Cancer Biology, Loyola University Chicago, Maywood, United StatesDepartment of Cancer Biology, Loyola University Chicago, Maywood, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesInstitute for Research in Immunology and Cancer, Université de Montréal, Montréal, CanadaBen May Department for Cancer Research, University of Chicago, Chicago, United StatesDepartment of Cancer Biology, Loyola University Chicago, Maywood, United StatesChemical 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 estrogen receptor alpha (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 (Laso) 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 Laso 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.https://elifesciences.org/articles/72512breast cancerY537S ESR1 Mutationantiestrogenhormone resistancedrug resistanceestrogen receptor degradation |
| spellingShingle | David J Hosfield Sandra Weber Nan-Sheng Li Madline Sauvage Carstyn F Joiner Govinda R Hancock Emily A Sullivan Estelle Ndukwe Ross Han Sydney Cush Muriel Lainé Sylvie C Mader Geoffrey L Greene Sean W Fanning Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells eLife breast cancer Y537S ESR1 Mutation antiestrogen hormone resistance drug resistance estrogen receptor degradation |
| title | Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells |
| title_full | Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells |
| title_fullStr | Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells |
| title_full_unstemmed | Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells |
| title_short | Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells |
| title_sort | stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in esr1 mutant breast cancer cells |
| topic | breast cancer Y537S ESR1 Mutation antiestrogen hormone resistance drug resistance estrogen receptor degradation |
| url | https://elifesciences.org/articles/72512 |
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