Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
22 09 2023
22 09 2023
Historique:
received:
17
07
2023
accepted:
20
09
2023
medline:
25
9
2023
pubmed:
23
9
2023
entrez:
22
9
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37739987
doi: 10.1038/s41598-023-43121-x
pii: 10.1038/s41598-023-43121-x
pmc: PMC10516926
doi:
Substances chimiques
Proteasome Endopeptidase Complex
EC 3.4.25.1
Proteasome Inhibitors
0
NF-E2-Related Factor 1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15843Subventions
Organisme : NCI NIH HHS
ID : P30 CA016059
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA246182
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132396
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
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