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Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer
Triple-negative breast cancer (TNBC) patients receive chemotherapy treatment, including doxorubicin, due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore, there is a need to identify biomarkers that determine effective drug response. A ph...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9547066/ https://www.ncbi.nlm.nih.gov/pubmed/36207498 http://dx.doi.org/10.1038/s41698-022-00313-4 |
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author | Velenosi, Thomas J. Krausz, Kristopher W. Hamada, Keisuke Dorsey, Tiffany H. Ambs, Stefan Takahashi, Shogo Gonzalez, Frank J. |
author_facet | Velenosi, Thomas J. Krausz, Kristopher W. Hamada, Keisuke Dorsey, Tiffany H. Ambs, Stefan Takahashi, Shogo Gonzalez, Frank J. |
author_sort | Velenosi, Thomas J. |
collection | PubMed |
description | Triple-negative breast cancer (TNBC) patients receive chemotherapy treatment, including doxorubicin, due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore, there is a need to identify biomarkers that determine effective drug response. A pharmacometabolomics study was performed using doxorubicin sensitive and resistant TNBC patient-derived xenograft (PDX) models to detect urinary metabolic biomarkers of treatment effectiveness. Evaluation of metabolite production was assessed by directly studying tumor levels in TNBC-PDX mice and human subjects. Metabolic flux leading to biomarker production was determined using stable isotope-labeled tracers in TNBC-PDX ex vivo tissue slices. Findings were validated in 12-h urine samples from control (n = 200), ER+/PR+ (n = 200), ER+/PR+/HER2+ (n = 36), HER2+ (n = 81) and TNBC (n = 200) subjects. Diacetylspermine was identified as a urine metabolite that robustly changed in response to effective doxorubicin treatment, which persisted after the final dose. Urine diacetylspermine was produced by the tumor and correlated with tumor volume. Ex vivo tumor slices revealed that doxorubicin directly increases diacetylspermine production by increasing tumor spermidine/spermine N(1)-acetyltransferase 1 expression and activity, which was corroborated by elevated polyamine flux. In breast cancer patients, tumor diacetylspermine was elevated compared to matched non-cancerous tissue and increased in HER2+ and TNBC compared to ER+ subtypes. Urine diacetylspermine was associated with breast cancer tumor volume and poor tumor grade. This study describes a pharmacometabolomics strategy for identifying cancer metabolic biomarkers that indicate drug response. Our findings characterize urine diacetylspermine as a non-invasive biomarker of doxorubicin effectiveness in TNBC. |
format | Online Article Text |
id | pubmed-9547066 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-95470662022-10-09 Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer Velenosi, Thomas J. Krausz, Kristopher W. Hamada, Keisuke Dorsey, Tiffany H. Ambs, Stefan Takahashi, Shogo Gonzalez, Frank J. NPJ Precis Oncol Article Triple-negative breast cancer (TNBC) patients receive chemotherapy treatment, including doxorubicin, due to the lack of targeted therapies. Drug resistance is a major cause of treatment failure in TNBC and therefore, there is a need to identify biomarkers that determine effective drug response. A pharmacometabolomics study was performed using doxorubicin sensitive and resistant TNBC patient-derived xenograft (PDX) models to detect urinary metabolic biomarkers of treatment effectiveness. Evaluation of metabolite production was assessed by directly studying tumor levels in TNBC-PDX mice and human subjects. Metabolic flux leading to biomarker production was determined using stable isotope-labeled tracers in TNBC-PDX ex vivo tissue slices. Findings were validated in 12-h urine samples from control (n = 200), ER+/PR+ (n = 200), ER+/PR+/HER2+ (n = 36), HER2+ (n = 81) and TNBC (n = 200) subjects. Diacetylspermine was identified as a urine metabolite that robustly changed in response to effective doxorubicin treatment, which persisted after the final dose. Urine diacetylspermine was produced by the tumor and correlated with tumor volume. Ex vivo tumor slices revealed that doxorubicin directly increases diacetylspermine production by increasing tumor spermidine/spermine N(1)-acetyltransferase 1 expression and activity, which was corroborated by elevated polyamine flux. In breast cancer patients, tumor diacetylspermine was elevated compared to matched non-cancerous tissue and increased in HER2+ and TNBC compared to ER+ subtypes. Urine diacetylspermine was associated with breast cancer tumor volume and poor tumor grade. This study describes a pharmacometabolomics strategy for identifying cancer metabolic biomarkers that indicate drug response. Our findings characterize urine diacetylspermine as a non-invasive biomarker of doxorubicin effectiveness in TNBC. Nature Publishing Group UK 2022-10-07 /pmc/articles/PMC9547066/ /pubmed/36207498 http://dx.doi.org/10.1038/s41698-022-00313-4 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Velenosi, Thomas J. Krausz, Kristopher W. Hamada, Keisuke Dorsey, Tiffany H. Ambs, Stefan Takahashi, Shogo Gonzalez, Frank J. Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer |
title | Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer |
title_full | Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer |
title_fullStr | Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer |
title_full_unstemmed | Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer |
title_short | Pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer |
title_sort | pharmacometabolomics reveals urinary diacetylspermine as a biomarker of doxorubicin effectiveness in triple negative breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9547066/ https://www.ncbi.nlm.nih.gov/pubmed/36207498 http://dx.doi.org/10.1038/s41698-022-00313-4 |
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