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The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells
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 vers...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335054/ https://www.ncbi.nlm.nih.gov/pubmed/30489256 http://dx.doi.org/10.7554/eLife.37161 |
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author | Fanning, Sean W Jeselsohn, Rinath Dharmarajan, Venkatasubramanian Mayne, Christopher G Karimi, Mostafa Buchwalter, Gilles Houtman, René Toy, Weiyi Fowler, Colin E Han, Ross Lainé, Muriel Carlson, Kathryn E Martin, Teresa A Nowak, Jason Nwachukwu, Jerome C Hosfield, David J Chandarlapaty, Sarat Tajkhorshid, Emad Nettles, Kendall W Griffin, Patrick R Shen, Yang Katzenellenbogen, John A Brown, Myles Greene, Geoffrey L |
author_facet | Fanning, Sean W Jeselsohn, Rinath Dharmarajan, Venkatasubramanian Mayne, Christopher G Karimi, Mostafa Buchwalter, Gilles Houtman, René Toy, Weiyi Fowler, Colin E Han, Ross Lainé, Muriel Carlson, Kathryn E Martin, Teresa A Nowak, Jason Nwachukwu, Jerome C Hosfield, David J Chandarlapaty, Sarat Tajkhorshid, Emad Nettles, Kendall W Griffin, Patrick R Shen, Yang Katzenellenbogen, John A Brown, Myles Greene, Geoffrey L |
author_sort | Fanning, Sean W |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-6335054 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-63350542019-01-24 The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells Fanning, Sean W Jeselsohn, Rinath Dharmarajan, Venkatasubramanian Mayne, Christopher G Karimi, Mostafa Buchwalter, Gilles Houtman, René Toy, Weiyi Fowler, Colin E Han, Ross Lainé, Muriel Carlson, Kathryn E Martin, Teresa A Nowak, Jason Nwachukwu, Jerome C Hosfield, David J Chandarlapaty, Sarat Tajkhorshid, Emad Nettles, Kendall W Griffin, Patrick R Shen, Yang Katzenellenbogen, John A Brown, Myles Greene, Geoffrey L eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2018-11-29 /pmc/articles/PMC6335054/ /pubmed/30489256 http://dx.doi.org/10.7554/eLife.37161 Text en © 2018, Fanning et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Fanning, Sean W Jeselsohn, Rinath Dharmarajan, Venkatasubramanian Mayne, Christopher G Karimi, Mostafa Buchwalter, Gilles Houtman, René Toy, Weiyi Fowler, Colin E Han, Ross Lainé, Muriel Carlson, Kathryn E Martin, Teresa A Nowak, Jason Nwachukwu, Jerome C Hosfield, David J Chandarlapaty, Sarat Tajkhorshid, Emad Nettles, Kendall W Griffin, Patrick R Shen, Yang Katzenellenbogen, John A Brown, Myles Greene, Geoffrey L The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells |
title | The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells |
title_full | The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells |
title_fullStr | The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells |
title_full_unstemmed | The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells |
title_short | The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells |
title_sort | serm/serd bazedoxifene disrupts esr1 helix 12 to overcome acquired hormone resistance in breast cancer cells |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335054/ https://www.ncbi.nlm.nih.gov/pubmed/30489256 http://dx.doi.org/10.7554/eLife.37161 |
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