Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance.

Abstract

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.

• Authors: Catalina Lodillinsky, Laetitia Fuhrmann, Marie Irondelle, Olena Pylypenko, Xiao-Yan Li, Hélène Bonsang-Kitzis, Fabien Reyal, Sophie Vacher, Claire Calmel, Olivier De Wever, Ivan Bièche, Marie-Lise Lacombe, Ana Maria Eiján, Anne Houdusse, Anne Vincent-Salomon, Stephen J Weiss, Philippe Chavrier, Mathieu Boissan
• Journal: Oncogene (Oncogene) Vol. 40 Issue 23 Pg. 4019-4032 (06 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 34012098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NM23 Nucleoside Diphosphate Kinases
• NME1 protein, human
• MMP14 protein, human
• Matrix Metalloproteinase 14
• DNM2 protein, human
• Dynamin II

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line
• Cell Movement (physiology)
• Dynamin II (metabolism)
• Extracellular Matrix (metabolism)
• Female
• Humans
• Matrix Metalloproteinase 14 (genetics, metabolism)
• Mice
• Mice, Nude
• Middle Aged
• NM23 Nucleoside Diphosphate Kinases (metabolism)
• Neoplasm Metastasis
• Neoplasm Staging
• Xenograft Model Antitumor Assays