Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells
Abstract Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-12-01
|
| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-022-00497-9 |
| _version_ | 1827775134358831104 |
|---|---|
| author | G. R. Hancock K. S. Young D. J. Hosfield C. Joiner E. A. Sullivan Y. Yildiz M. Lainé G. L. Greene S. W. Fanning |
| author_facet | G. R. Hancock K. S. Young D. J. Hosfield C. Joiner E. A. Sullivan Y. Yildiz M. Lainé G. L. Greene S. W. Fanning |
| author_sort | G. R. Hancock |
| collection | DOAJ |
| description | Abstract Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells. |
| first_indexed | 2024-03-11T13:47:45Z |
| format | Article |
| id | doaj.art-e634006f12244e7a85928336ed7747d2 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-11T13:47:45Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-e634006f12244e7a85928336ed7747d22023-11-02T10:12:02ZengNature Portfolionpj Breast Cancer2374-46772022-12-018112610.1038/s41523-022-00497-9Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cellsG. R. Hancock0K. S. Young1D. J. Hosfield2C. Joiner3E. A. Sullivan4Y. Yildiz5M. Lainé6G. L. Greene7S. W. Fanning8Department of Cancer Biology, Loyola University Chicago, Stritch School of MedicineDepartment of Cancer Biology, Loyola University Chicago, Stritch School of MedicineBen May Department for Cancer Research, University of ChicagoDepartment of Cancer Biology, Loyola University Chicago, Stritch School of MedicineDepartment of Cancer Biology, Loyola University Chicago, Stritch School of MedicineDepartment of Cancer Biology, Loyola University Chicago, Stritch School of MedicineBen May Department for Cancer Research, University of ChicagoBen May Department for Cancer Research, University of ChicagoDepartment of Cancer Biology, Loyola University Chicago, Stritch School of MedicineAbstract Estrogen receptor alpha (ERα) is a ligand-dependent master transcriptional regulator and key driver of breast cancer pathology. Small molecule hormones and competitive antagonists favor unique ERα conformational ensembles that elicit ligand-specific transcriptional programs in breast cancer and other hormone-responsive tissues. By affecting disparate ligand binding domain structural features, unconventional ligand scaffolds can redirect ERα genomic binding patterns to engage novel therapeutic transcriptional programs. To improve our understanding of these ERα structure-transcriptional relationships, we develop a series of chemically unconventional antagonists based on the antiestrogens elacestrant and lasofoxifene. High-resolution x-ray co-crystal structures show that these molecules affect both classical and unique structural motifs within the ERα ligand binding pocket. They show moderately reduced antagonistic potencies on ERα genomic activities but are effective anti-proliferative agents in luminal breast cancer cells. Interestingly, they favor a 4-hydroxytamoxifen-like accumulation of ERα in breast cancer cells but lack uterotrophic activities in an endometrial cell line. Importantly, RNA sequencing shows that the lead molecules engage transcriptional pathways similar to the selective estrogen receptor degrader fulvestrant. This advance shows that fulvestrant-like genomic activities can be achieved without affecting ERα accumulation in breast cancer cells.https://doi.org/10.1038/s41523-022-00497-9 |
| spellingShingle | G. R. Hancock K. S. Young D. J. Hosfield C. Joiner E. A. Sullivan Y. Yildiz M. Lainé G. L. Greene S. W. Fanning Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells npj Breast Cancer |
| title | Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells |
| title_full | Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells |
| title_fullStr | Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells |
| title_full_unstemmed | Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells |
| title_short | Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells |
| title_sort | unconventional isoquinoline based serms elicit fulvestrant like transcriptional programs in er breast cancer cells |
| url | https://doi.org/10.1038/s41523-022-00497-9 |
| work_keys_str_mv | AT grhancock unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT ksyoung unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT djhosfield unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT cjoiner unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT easullivan unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT yyildiz unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT mlaine unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT glgreene unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells AT swfanning unconventionalisoquinolinebasedsermselicitfulvestrantliketranscriptionalprogramsinerbreastcancercells |