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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...

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Autores principales: Traphagen, Nicole A., Hosford, Sarah R., Jiang, Amanda, Marotti, Jonathan D., Brauer, Brooke L., Demidenko, Eugene, Miller, Todd W.
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
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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.
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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
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