Targeting MUC1-C Suppresses Chronic Activation of Cytosolic Nucleotide Receptors and STING in Triple-Negative Breast Cancer.
ISG15
MUC1-C
STING
TNBC
cGAS
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
24 May 2022
24 May 2022
Historique:
received:
01
04
2022
revised:
11
05
2022
accepted:
19
05
2022
entrez:
10
6
2022
pubmed:
11
6
2022
medline:
11
6
2022
Statut:
epublish
Résumé
The MUC1-C apical transmembrane protein is activated in the acute response of epithelial cells to inflammation. However, chronic MUC1-C activation promotes cancer progression, emphasizing the importance of MUC1-C as a target for treatment. We report here that MUC1-C is necessary for intrinsic expression of the RIG-I, MDA5 and cGAS cytosolic nucleotide pattern recognition receptors (PRRs) and the cGAS-stimulator of IFN genes (STING) in triple-negative breast cancer (TNBC) cells. Consistent with inducing the PRR/STING axis, MUC1-C drives chronic IFN-β production and activation of the type I interferon (IFN) pathway. MUC1-C thereby induces the IFN-related DNA damage resistance gene signature (IRDS), which includes ISG15, in linking chronic inflammation with DNA damage resistance. Targeting MUC1-C in TNBC cells treated with carboplatin or the PARP inhibitor olaparib further demonstrated that MUC1-C is necessary for expression of PRRs, STING and ISG15 and for intrinsic DNA damage resistance. Of translational relevance, MUC1 significantly associates with upregulation of STING and ISG15 in TNBC tumors and is a target for treatment with CAR T cells, antibody-drug conjugates (ADCs) and direct inhibitors that are under preclinical and clinical development.
Identifiants
pubmed: 35681561
pii: cancers14112580
doi: 10.3390/cancers14112580
pmc: PMC9179855
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : NCI NIH HHS
ID : U24 CA232979
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA097098
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166480
Pays : United States
Organisme : NCI NIH HHS
ID : CA232979
Pays : United States
Organisme : NCI NIH HHS
ID : CA097098
Pays : United States
Organisme : NCI NIH HHS
ID : CA233084
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA233084
Pays : United States
Organisme : NCI NIH HHS
ID : CA166480
Pays : United States
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