Inhibition of ERK signaling for treatment of ERRα positive TNBC
Breast cancer is the second leading cause of cancer-related deaths in women and triple-negative breast cancer (TNBC), in particular, is an aggressive and highly metastatic type of breast cancer that does not respond to established targeted therapies and is associated with poor prognosis and worse su...
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| Veröffentlicht in: | PloS one 2023-05, Vol.18 (5), p.e0283047 |
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| creator | Musheyev, David Miller, Esther Birnbaum, Natania Miller, Elisheva Erblich, Shoshana Schuck, Alyssa Alayev, Anya |
| description | Breast cancer is the second leading cause of cancer-related deaths in women and triple-negative breast cancer (TNBC), in particular, is an aggressive and highly metastatic type of breast cancer that does not respond to established targeted therapies and is associated with poor prognosis and worse survival. Previous studies identified a subgroup of triple-negative breast cancer patients with high expression of estrogen related receptor alpha (ERRα) that has better prognosis when treated with tamoxifen. We therefore set out to identify common targets of tamoxifen and ERRα in the context of TNBC using phosphoproteomic analysis. In this study, we discovered that phosphorylation of mitogen-activated protein kinase 1 (MAPK1) is regulated by tamoxifen as well as ERRα. Additionally, we showed that inhibition of MAPK signaling together with the use of a selective ERRα inverse agonist, XCT-790, leads to a significant upregulation of apoptosis and paves way for the therapeutic use of MAPK inhibitors for treatment of ERRα expressing TNBC. |
| doi_str_mv | 10.1371/journal.pone.0283047 |
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Previous studies identified a subgroup of triple-negative breast cancer patients with high expression of estrogen related receptor alpha (ERRα) that has better prognosis when treated with tamoxifen. We therefore set out to identify common targets of tamoxifen and ERRα in the context of TNBC using phosphoproteomic analysis. In this study, we discovered that phosphorylation of mitogen-activated protein kinase 1 (MAPK1) is regulated by tamoxifen as well as ERRα. Additionally, we showed that inhibition of MAPK signaling together with the use of a selective ERRα inverse agonist, XCT-790, leads to a significant upregulation of apoptosis and paves way for the therapeutic use of MAPK inhibitors for treatment of ERRα expressing TNBC.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0283047</identifier><identifier>PMID: 37163498</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>African Americans ; Antibodies ; Apoptosis ; Biology and life sciences ; Breast cancer ; Cancer therapies ; Cell Line, Tumor ; Cell Proliferation ; Chemotherapy ; Drug Inverse Agonism ; ERRalpha Estrogen-Related Receptor ; Estrogens ; Female ; Humans ; Inverse agonists ; Kinases ; MAP kinase ; Medical prognosis ; Medicine and Health Sciences ; Metabolism ; Metastases ; Metastasis ; Mortality ; Phosphatase ; Phosphorylation ; Prognosis ; Proteins ; Receptors, Estrogen - metabolism ; Research and Analysis Methods ; Signaling ; Subgroups ; Tamoxifen ; Tamoxifen - pharmacology ; Tamoxifen - therapeutic use ; Target recognition ; Triple Negative Breast Neoplasms - pathology ; Tumors ; Womens health</subject><ispartof>PloS one, 2023-05, Vol.18 (5), p.e0283047</ispartof><rights>Copyright: © 2023 Musheyev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>2023 Musheyev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Musheyev et al 2023 Musheyev et al</rights><rights>2023 Musheyev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c476t-98903479ffe760cdc8a5505758d4dae01ec62b912c816e277335b0c739b177713</cites><orcidid>0000-0002-2702-1763 ; 0000-0001-6235-5729</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10171695/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10171695/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37163498$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Musheyev, David</creatorcontrib><creatorcontrib>Miller, Esther</creatorcontrib><creatorcontrib>Birnbaum, Natania</creatorcontrib><creatorcontrib>Miller, Elisheva</creatorcontrib><creatorcontrib>Erblich, Shoshana</creatorcontrib><creatorcontrib>Schuck, Alyssa</creatorcontrib><creatorcontrib>Alayev, Anya</creatorcontrib><title>Inhibition of ERK signaling for treatment of ERRα positive TNBC</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Breast cancer is the second leading cause of cancer-related deaths in women and triple-negative breast cancer (TNBC), in particular, is an aggressive and highly metastatic type of breast cancer that does not respond to established targeted therapies and is associated with poor prognosis and worse survival. Previous studies identified a subgroup of triple-negative breast cancer patients with high expression of estrogen related receptor alpha (ERRα) that has better prognosis when treated with tamoxifen. We therefore set out to identify common targets of tamoxifen and ERRα in the context of TNBC using phosphoproteomic analysis. In this study, we discovered that phosphorylation of mitogen-activated protein kinase 1 (MAPK1) is regulated by tamoxifen as well as ERRα. Additionally, we showed that inhibition of MAPK signaling together with the use of a selective ERRα inverse agonist, XCT-790, leads to a significant upregulation of apoptosis and paves way for the therapeutic use of MAPK inhibitors for treatment of ERRα expressing TNBC.</description><subject>African Americans</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Biology and life sciences</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Chemotherapy</subject><subject>Drug Inverse Agonism</subject><subject>ERRalpha Estrogen-Related Receptor</subject><subject>Estrogens</subject><subject>Female</subject><subject>Humans</subject><subject>Inverse agonists</subject><subject>Kinases</subject><subject>MAP kinase</subject><subject>Medical prognosis</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mortality</subject><subject>Phosphatase</subject><subject>Phosphorylation</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Receptors, Estrogen - 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| subjects | African Americans Antibodies Apoptosis Biology and life sciences Breast cancer Cancer therapies Cell Line, Tumor Cell Proliferation Chemotherapy Drug Inverse Agonism ERRalpha Estrogen-Related Receptor Estrogens Female Humans Inverse agonists Kinases MAP kinase Medical prognosis Medicine and Health Sciences Metabolism Metastases Metastasis Mortality Phosphatase Phosphorylation Prognosis Proteins Receptors, Estrogen - metabolism Research and Analysis Methods Signaling Subgroups Tamoxifen Tamoxifen - pharmacology Tamoxifen - therapeutic use Target recognition Triple Negative Breast Neoplasms - pathology Tumors Womens health |
| title | Inhibition of ERK signaling for treatment of ERRα positive TNBC |
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