Cargando…
High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer
Estrogen receptor alpha (ER)-positive breast cancer is commonly treated with endocrine therapies, including anti-estrogens that bind and inhibit ER activity, and aromatase inhibitors that suppress estrogen biosynthesis to inhibit estrogen-dependent ER activity. Paradoxically, treatment with estrogen...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122072/ https://www.ncbi.nlm.nih.gov/pubmed/33875787 http://dx.doi.org/10.1038/s41388-021-01782-w |
_version_ | 1783692511740428288 |
---|---|
author | Traphagen, Nicole A. Hosford, Sarah R. Jiang, Amanda Marotti, Jonathan D. Brauer, Brooke L. Demidenko, Eugene Miller, Todd W. |
author_facet | Traphagen, Nicole A. Hosford, Sarah R. Jiang, Amanda Marotti, Jonathan D. Brauer, Brooke L. Demidenko, Eugene Miller, Todd W. |
author_sort | Traphagen, Nicole A. |
collection | PubMed |
description | Estrogen receptor alpha (ER)-positive breast cancer is commonly treated with endocrine therapies, including anti-estrogens that bind and inhibit ER activity, and aromatase inhibitors that suppress estrogen biosynthesis to inhibit estrogen-dependent ER activity. Paradoxically, treatment with estrogens such as 17b-estradiol can also be effective against ER+ breast cancer. Despite the known efficacy of estrogen therapy, the lack of a predictive biomarker of response and understanding of the mechanism of action have contributed to its limited clinical use. Herein, we demonstrate that ER overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer. |
format | Online Article Text |
id | pubmed-8122072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
record_format | MEDLINE/PubMed |
spelling | pubmed-81220722021-10-19 High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer Traphagen, Nicole A. Hosford, Sarah R. Jiang, Amanda Marotti, Jonathan D. Brauer, Brooke L. Demidenko, Eugene Miller, Todd W. Oncogene Article Estrogen receptor alpha (ER)-positive breast cancer is commonly treated with endocrine therapies, including anti-estrogens that bind and inhibit ER activity, and aromatase inhibitors that suppress estrogen biosynthesis to inhibit estrogen-dependent ER activity. Paradoxically, treatment with estrogens such as 17b-estradiol can also be effective against ER+ breast cancer. Despite the known efficacy of estrogen therapy, the lack of a predictive biomarker of response and understanding of the mechanism of action have contributed to its limited clinical use. Herein, we demonstrate that ER overexpression confers resistance to estrogen deprivation through ER activation in human ER+ breast cancer cells and xenografts grown in mice. However, ER overexpression and the associated high levels of ER transcriptional activation converted 17b-estradiol from a growth-promoter to a growth-suppressor, offering a targetable therapeutic vulnerability and a potential means of identifying patients likely to benefit from estrogen therapy. Since ER+ breast cancer cells and tumors ultimately developed resistance to continuous estrogen deprivation or continuous 17b-estradiol treatment, we tested schedules of alternating treatments. Oscillation of ER activity through cycling of 17b-estradiol and estrogen deprivation provided long-term control of patient-derived xenografts, offering a novel endocrine-only strategy to manage ER+ breast cancer. 2021-04-19 2021-05 /pmc/articles/PMC8122072/ /pubmed/33875787 http://dx.doi.org/10.1038/s41388-021-01782-w Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Traphagen, Nicole A. Hosford, Sarah R. Jiang, Amanda Marotti, Jonathan D. Brauer, Brooke L. Demidenko, Eugene Miller, Todd W. High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer |
title | High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer |
title_full | High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer |
title_fullStr | High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer |
title_full_unstemmed | High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer |
title_short | High estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer |
title_sort | high estrogen receptor alpha activation confers resistance to estrogen deprivation and is required for therapeutic response to estrogen in breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122072/ https://www.ncbi.nlm.nih.gov/pubmed/33875787 http://dx.doi.org/10.1038/s41388-021-01782-w |
work_keys_str_mv | AT traphagennicolea highestrogenreceptoralphaactivationconfersresistancetoestrogendeprivationandisrequiredfortherapeuticresponsetoestrogeninbreastcancer AT hosfordsarahr highestrogenreceptoralphaactivationconfersresistancetoestrogendeprivationandisrequiredfortherapeuticresponsetoestrogeninbreastcancer AT jiangamanda highestrogenreceptoralphaactivationconfersresistancetoestrogendeprivationandisrequiredfortherapeuticresponsetoestrogeninbreastcancer AT marottijonathand highestrogenreceptoralphaactivationconfersresistancetoestrogendeprivationandisrequiredfortherapeuticresponsetoestrogeninbreastcancer AT brauerbrookel highestrogenreceptoralphaactivationconfersresistancetoestrogendeprivationandisrequiredfortherapeuticresponsetoestrogeninbreastcancer AT demidenkoeugene highestrogenreceptoralphaactivationconfersresistancetoestrogendeprivationandisrequiredfortherapeuticresponsetoestrogeninbreastcancer AT millertoddw highestrogenreceptoralphaactivationconfersresistancetoestrogendeprivationandisrequiredfortherapeuticresponsetoestrogeninbreastcancer |