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.
Highlights
Ductal carcinoma in situ (DCIS) correspond to the proliferation of neoplastic breast epithelial cells contained within a layer of myoepithelial cells and an intact basementUniversity Sorbonne, Paris, France Laboratory of Experimental Cancer Research, Cancer ResearchInstitute Ghent (CRIG), Department of Human Structure and Repair, Ghent University, Ghent, Belgium Laboratory of Biochemistry and Hormonology, Tenon Hospital, AP-HP, Paris, France Present address: Gynecological and Breast Surgery and Cancerology Center, RAMSAY-Générale de Santé, Hôpital Privé des Peupliers, Paris, France membrane [1]
We recently reported that human NME1 interacts with and supplies dynamin with high GTP levels required for membrane fission and, promotes endocytosis and clearance of cell surface receptors [8, 9]
NME expression was investigated by IHC analysis on whole sections and on a tissue microarray (TMA) of synchronous DCIS and invasive breast cancer (IBC) foci from 156 breast cancer patient samples using specific NME1 pAb and NME2 mAb with no cross-reactivity (Supplementary Fig. S1 and Table S2)
Summary
Ductal carcinoma in situ (DCIS) correspond to the proliferation of neoplastic breast epithelial cells contained within a layer of myoepithelial cells and an intact basement. Some DCIS (20–50%) will progress to invasive breast cancer (IBC) with characteristic tumor cell dissemination and poor outcome [1]. We recently reported that human NME1 interacts with and supplies dynamin with high GTP levels required for membrane fission and, promotes endocytosis and clearance of cell surface receptors [8, 9]. NME2 expression, which was up-regulated in DCIS, remained high in IBCs. The ability of NME1 or NME2 to influence tumor invasion was evaluated using the intraductal xenograft model involving the injection of human MCF10DCIS. We found a specific association of NME1 with endocytic clathrin-coated structures and a regulation of MT1-MMP surface levels by dynamin downstream of NME1, clarifying the mechanism underlying the increased invasive potential of breast cancer cells during the DCIS-to-IBC transition
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