Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance.
Animals
Breast Neoplasms
/ genetics
Cell Line
Cell Movement
/ physiology
Dynamin II
/ metabolism
Extracellular Matrix
/ metabolism
Female
Humans
Matrix Metalloproteinase 14
/ genetics
Mice
Mice, Nude
Middle Aged
NM23 Nucleoside Diphosphate Kinases
/ metabolism
Neoplasm Metastasis
Neoplasm Staging
Xenograft Model Antitumor Assays
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
07
10
2020
accepted:
27
04
2021
revised:
13
04
2021
pubmed:
21
5
2021
medline:
14
1
2022
entrez:
20
5
2021
Statut:
ppublish
Résumé
Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.
Identifiants
pubmed: 34012098
doi: 10.1038/s41388-021-01826-1
pii: 10.1038/s41388-021-01826-1
pmc: PMC8195739
doi:
Substances chimiques
NM23 Nucleoside Diphosphate Kinases
0
NME1 protein, human
EC 2.7.4.6
MMP14 protein, human
EC 3.4.24.80
Matrix Metalloproteinase 14
EC 3.4.24.80
DNM2 protein, human
EC 3.6.5.5
Dynamin II
EC 3.6.5.5
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
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