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Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant
BACKGROUND: Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methyl...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139055/ https://www.ncbi.nlm.nih.gov/pubmed/34020697 http://dx.doi.org/10.1186/s13058-021-01433-8 |
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author | Jacquemetton, Julien Kassem, Loay Poulard, Coralie Dahmani, Ahmed De Plater, Ludmilla Montaudon, Elodie Sourd, Laura Morisset, Ludivine El Botty, Rania Chateau-Joubert, Sophie Vacher, Sophie Biche, Ivan Treilleux, Isabelle Trdan, Olivier Marangoni, Elisabetta Le Romancer, Muriel |
author_facet | Jacquemetton, Julien Kassem, Loay Poulard, Coralie Dahmani, Ahmed De Plater, Ludmilla Montaudon, Elodie Sourd, Laura Morisset, Ludivine El Botty, Rania Chateau-Joubert, Sophie Vacher, Sophie Biche, Ivan Treilleux, Isabelle Trdan, Olivier Marangoni, Elisabetta Le Romancer, Muriel |
author_sort | Jacquemetton, Julien |
collection | PubMed |
description | BACKGROUND: Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. METHODS: The interaction of ER/Src and ER/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ER+ and 3 ER PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. RESULTS: We confirmed that ER/Src and ER/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER signaling, since genomic degradation of ER was unaltered in these tumors, whereas the treatment did not diminish the level of ER/PI3K interaction. Interestingly, in 2 ER models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER/PI3K interaction. CONCLUSIONS: Our results demonstrate that ER/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER+ tumors was associated with a lack of impairment of ER/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER/PI3K in ER tumors could constitute a promising therapeutic option. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-021-01433-8. |
format | Online Article Text |
id | pubmed-8139055 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-81390552021-05-21 Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant Jacquemetton, Julien Kassem, Loay Poulard, Coralie Dahmani, Ahmed De Plater, Ludmilla Montaudon, Elodie Sourd, Laura Morisset, Ludivine El Botty, Rania Chateau-Joubert, Sophie Vacher, Sophie Biche, Ivan Treilleux, Isabelle Trdan, Olivier Marangoni, Elisabetta Le Romancer, Muriel Breast Cancer Res Research Article BACKGROUND: Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. METHODS: The interaction of ER/Src and ER/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ER+ and 3 ER PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. RESULTS: We confirmed that ER/Src and ER/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER signaling, since genomic degradation of ER was unaltered in these tumors, whereas the treatment did not diminish the level of ER/PI3K interaction. Interestingly, in 2 ER models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER/PI3K interaction. CONCLUSIONS: Our results demonstrate that ER/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER+ tumors was associated with a lack of impairment of ER/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER/PI3K in ER tumors could constitute a promising therapeutic option. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-021-01433-8. BioMed Central 2021-05-21 2021 /pmc/articles/PMC8139055/ /pubmed/34020697 http://dx.doi.org/10.1186/s13058-021-01433-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Jacquemetton, Julien Kassem, Loay Poulard, Coralie Dahmani, Ahmed De Plater, Ludmilla Montaudon, Elodie Sourd, Laura Morisset, Ludivine El Botty, Rania Chateau-Joubert, Sophie Vacher, Sophie Biche, Ivan Treilleux, Isabelle Trdan, Olivier Marangoni, Elisabetta Le Romancer, Muriel Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant |
title | Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant |
title_full | Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant |
title_fullStr | Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant |
title_full_unstemmed | Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant |
title_short | Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant |
title_sort | analysis of genomic and non-genomic signaling of estrogen receptor in pdx models of breast cancer treated with a combination of the pi3k inhibitor alpelisib (byl719) and fulvestrant |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139055/ https://www.ncbi.nlm.nih.gov/pubmed/34020697 http://dx.doi.org/10.1186/s13058-021-01433-8 |
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