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Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells

dc.contributor.authorFontanil T.
dc.contributor.authorálvarez-Teijeiro S.
dc.contributor.authorVillaronga M.Á.
dc.contributor.authorMohamedi Y.
dc.contributor.authorSolares L.
dc.contributor.authorMoncada-Pazos A.
dc.contributor.authorVega J.A.
dc.contributor.authorGarcía-Suárez O.
dc.contributor.authorPérez-Basterrechea M.
dc.contributor.authorGarcía-Pedrero J.M.
dc.contributor.authorObaya A.J.
dc.contributor.authorCal S.
dc.date.accessioned2020-09-02T22:17:56Z
dc.date.available2020-09-02T22:17:56Z
dc.date.issued2017
dc.identifier10.18632/oncotarget.14627
dc.identifier.citation8, 8, 13716-13729
dc.identifier.issn19492553
dc.identifier.urihttps://hdl.handle.net/20.500.12728/4509
dc.descriptionFibulin-2 participates in the assembly of extracellular matrix components through interactions with multiple ligands and promotes contacts between cells and their surrounding environment. Consequently, identification of processes that could lead to an altered Fibulin-2 could have a major impact not only in the maintenance of tissue architecture and morphogenesis but also in pathological situations including cancer. Herein, we have investigated the ability of the secreted metalloproteases ADAMTS-4 and ADAMTS-5 to digest Fibulin-2. Using in vitro approaches and cultured breast cancer cell lines we demonstrate that Fibulin-2 is a better substrate for ADAMTS-5 than it is for ADAMTS-4. Moreover, Fibulin-2 degradation is associated to an enhancement of the invasive potential of T47D, MCF-7 and SK-BR-3 cells. We have also found that conditioned medium from MCF-7 cells that simultaneously overexpress Fibulin-2 and ADAMTS-5 significantly induced the migratory and invasive ability of normal breast fibroblasts using 3D collagen matrices. Immunohistochemical analysis highlights the close proximity or partial overlap of both Fibulin-2 and ADAMTS-5 in breast tumor samples. Additionally, proteolytic products derived from a potential degradation of Fibulin-2 by ADAMTS-5 were also identified in these samples. Finally, we also show that the cleavage of Fibulin-2 by ADAMTS-5 is counteracted by ADAMTS-12, a metalloprotease that interacts with Fibulin-2. Overall, our results provide direct evidence indicating that Fibulin-2 is a novel substrate of ADAMTS-5 and that this proteolysis could alter the cellular microenvironment affecting the balance between protumor and antitumor effects associated to both Fibulin-2 and the ADAMTSs metalloproteases.
dc.language.isoen
dc.publisherImpact Journals LLC
dc.subjectADAMTS
dc.subjectAggrecanases
dc.subjectExtracellular matrix
dc.subjectFibulin
dc.subjectMetalloproteases
dc.subjectaggrecanase
dc.subjectaggrecanase 1
dc.subjectaggrecanase 2
dc.subjectfibulin
dc.subjectfibulin 2
dc.subjectunclassified drug
dc.subjectArticle
dc.subjectbreast cancer cell line
dc.subjectbreast carcinogenesis
dc.subjectcell invasion
dc.subjectcell migration
dc.subjectcontrolled study
dc.subjectfibroblast
dc.subjecthuman
dc.subjecthuman cell
dc.subjectimmunohistochemistry
dc.subjectin vitro study
dc.subjectmolecular pathology
dc.subjectprotein cleavage
dc.subjectprotein degradation
dc.subjectprotein determination
dc.subjectprotein expression
dc.subjectprotein function
dc.titleCleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells
dc.typeArticle


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