Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
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
_version_ 1783387829410201600
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
work_keys_str_mv AT fanningseanw thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT jeselsohnrinath thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT dharmarajanvenkatasubramanian thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT maynechristopherg thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT karimimostafa thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT buchwaltergilles thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT houtmanrene thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT toyweiyi thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT fowlercoline thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT hanross thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT lainemuriel thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT carlsonkathryne thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT martinteresaa thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT nowakjason thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT nwachukwujeromec thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT hosfielddavidj thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT chandarlapatysarat thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT tajkhorshidemad thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT nettleskendallw thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT griffinpatrickr thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT shenyang thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT katzenellenbogenjohna thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT brownmyles thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT greenegeoffreyl thesermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT fanningseanw sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT jeselsohnrinath sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT dharmarajanvenkatasubramanian sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT maynechristopherg sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT karimimostafa sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT buchwaltergilles sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT houtmanrene sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT toyweiyi sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT fowlercoline sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT hanross sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT lainemuriel sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT carlsonkathryne sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT martinteresaa sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT nowakjason sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT nwachukwujeromec sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT hosfielddavidj sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT chandarlapatysarat sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT tajkhorshidemad sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT nettleskendallw sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT griffinpatrickr sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT shenyang sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT katzenellenbogenjohna sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT brownmyles sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells
AT greenegeoffreyl sermserdbazedoxifenedisruptsesr1helix12toovercomeacquiredhormoneresistanceinbreastcancercells