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Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer

Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets...

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Autores principales: Byers, Holly A., Brooks, Amy N., Vangala, Janakiram R., Grible, Jacqueline M., Feygin, Alex, Clevenger, Charles V., Harrell, J. Chuck, Radhakrishnan, Senthil K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516926/
https://www.ncbi.nlm.nih.gov/pubmed/37739987
http://dx.doi.org/10.1038/s41598-023-43121-x
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author Byers, Holly A.
Brooks, Amy N.
Vangala, Janakiram R.
Grible, Jacqueline M.
Feygin, Alex
Clevenger, Charles V.
Harrell, J. Chuck
Radhakrishnan, Senthil K.
author_facet Byers, Holly A.
Brooks, Amy N.
Vangala, Janakiram R.
Grible, Jacqueline M.
Feygin, Alex
Clevenger, Charles V.
Harrell, J. Chuck
Radhakrishnan, Senthil K.
author_sort Byers, Holly A.
collection PubMed
description Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue. Although these observations suggest a pan-breast cancer utility for proteasome inhibitors, our further experiments with breast cancer cell lines and patient-derived xenografts (PDX) pointed to triple-negative breast cancer (TNBC) as the most sensitive subtype to proteasome inhibition. Finally, using TNBC cells, we extended our studies to in vivo xenograft experiments. Our previous work has firmly established a cytoprotective role for the transcription factor NRF1 via its ability to upregulate proteasome genes in response to proteasome inhibition. In further support of this notion, we show here that NRF1 depletion significantly reduced tumor burden in an MDA-MB-231 TNBC xenograft mouse model treated with carfilzomib. Taken together, our results point to TNBC as a particularly vulnerable breast cancer subtype to proteasome inhibition and provide a proof-of-principle for targeting NRF1 as a viable means to increase the efficacy of proteasome inhibitors in TNBC tumors.
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spelling pubmed-105169262023-09-24 Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer Byers, Holly A. Brooks, Amy N. Vangala, Janakiram R. Grible, Jacqueline M. Feygin, Alex Clevenger, Charles V. Harrell, J. Chuck Radhakrishnan, Senthil K. Sci Rep Article Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue. Although these observations suggest a pan-breast cancer utility for proteasome inhibitors, our further experiments with breast cancer cell lines and patient-derived xenografts (PDX) pointed to triple-negative breast cancer (TNBC) as the most sensitive subtype to proteasome inhibition. Finally, using TNBC cells, we extended our studies to in vivo xenograft experiments. Our previous work has firmly established a cytoprotective role for the transcription factor NRF1 via its ability to upregulate proteasome genes in response to proteasome inhibition. In further support of this notion, we show here that NRF1 depletion significantly reduced tumor burden in an MDA-MB-231 TNBC xenograft mouse model treated with carfilzomib. Taken together, our results point to TNBC as a particularly vulnerable breast cancer subtype to proteasome inhibition and provide a proof-of-principle for targeting NRF1 as a viable means to increase the efficacy of proteasome inhibitors in TNBC tumors. Nature Publishing Group UK 2023-09-22 /pmc/articles/PMC10516926/ /pubmed/37739987 http://dx.doi.org/10.1038/s41598-023-43121-x Text en © The Author(s) 2023 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 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/) .
spellingShingle Article
Byers, Holly A.
Brooks, Amy N.
Vangala, Janakiram R.
Grible, Jacqueline M.
Feygin, Alex
Clevenger, Charles V.
Harrell, J. Chuck
Radhakrishnan, Senthil K.
Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer
title Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer
title_full Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer
title_fullStr Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer
title_full_unstemmed Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer
title_short Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer
title_sort evaluation of the nrf1-proteasome axis as a therapeutic target in breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516926/
https://www.ncbi.nlm.nih.gov/pubmed/37739987
http://dx.doi.org/10.1038/s41598-023-43121-x
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