title: Cancer cell-associated MT1-MMP promotes blood vessel invasion and distant metastasis in triple-negative mammary tumors.
abstract: Functional roles for the cancer cell-associated membrane type I matrix metalloproteinase (MT1-MMP) during early steps of the metastatic cascade in primary tumors remain unresolved. In an effort to determine its significance, we determined the in vivo effects of RNAi-mediated downregulation in mammary cancer cells on the migration, blood and lymphatic vessel invasion (LVI), and lymph node and lung metastasis. We also correlated the expression of cancer cell MT1-MMP with blood vessel invasion (BVI) in 102 breast cancer biopsies. MT1-MMP downregulation in cancer cells decreased lung metastasis without affecting primary tumor growth. The inhibition of lung metastasis correlated with reduced cancer cell migration and BVI. Furthermore, cancer cell-expressed MT1-MMP upregulated the expression of MT1-MMP in vascular endothelial cells, but did not affect MT1-MMP expression in lymphatic endothelial cells, LVI, or lymph node metastasis. Of clinical importance, we observed that elevated MT1-MMP expression correlated with BVI in biopsies from triple-negative breast cancers (TNBC), which have a poor prognosis and high incidence of distant metastasis, relative to other breast cancer subtypes. Together, our findings established that MT1-MMP activity in breast tumors is essential for BVI, but not LVI, and that MT1-MMP should be further explored as a predictor and therapeutic target of hematogenous metastasis in TNBC patients.
authors.affiliation: Edwin L Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Molecular Pathology Unit, MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Perentes
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Kirkpatrick
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagano
authors.forename: Eve Y
authors.initials: EY
authors.lastname: Smith
authors.forename: Christine M
authors.initials: CM
authors.lastname: Shaver
authors.forename: Dennis
authors.initials: D
authors.lastname: Sgroi
authors.forename: Igor
authors.initials: I
authors.lastname: Garkavtsev
authors.forename: Lance L
authors.initials: LL
authors.lastname: Munn
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000172:deficiency; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000172:deficiency
chemical_list: D053511:Matrix Metalloproteinase 14; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C507086:MMP14 protein, human