title: The type I collagen induction of MT1-MMP-mediated MMP-2 activation is repressed by alphaVbeta3 integrin in human breast cancer cells.
abstract: The influence of alphaVbeta3 integrin on MT1-MMP functionality was studied in human breast cancer cells of differing beta3 integrin status. Overexpression of beta3 integrin caused increased cell surface expression of alphaV integrin and increased cellular adhesion to extracellular matrix (ECM) substrates in BT-549, MDA-MB-231 and MCF-7 cells. beta3 integrin expression also enhanced the migration of breast cancer cells on ECM substrates and enhanced collagen gel contraction. In vivo, alphaVbeta3 cooperated with MT1-MMP to increase the growth of MCF-7 cells after orthotopic inoculation in immunocompromised mice, but had no influence on in vitro proliferation. Despite these stimulatory effects, overexpression of beta3 integrin suppressed the type I collagen (Col I) induced MMP-2 activation in all breast cancer cell lines analyzed. This was also evident in extracts from the MCF-7 tumors in vivo, where MMP-2 activation was stimulated by MT1-MMP transfection, but attenuated with beta3 integrin expression. Although our studies confirm important biological effects of alphaVbeta3 integrin on enhancing cell adhesion and migration, ECM remodeling and tumor growth, beta3 integrin caused reduced MMP-2 activation in response to Col I in vitro, which appears to be physiologically relevant, as it was also seen in tumor xenografts in vivo. The reduction of MMP-2 activation (and thus MT1-MMP activity) by alphaVbeta3 in response to Col I may be important in scenarios where cells which are activated for matrix degradation need to preserve some pericellular collagen, perhaps as a substrate for cell adhesion and migration, thus maintaining a balanced level of proteolysis required for efficient tumor growth.
authors.affiliation: University of Melbourne, Department of Surgery, St Vincent's Hospital, Fitzroy, Victoria, 3065, Australia.
authors.forename: Kulrut
authors.initials: K
authors.lastname: Borrirukwanit
authors.forename: Marc A
authors.initials: MA
authors.lastname: Lafleur
authors.forename: Francesca A
authors.initials: FA
authors.lastname: Mercuri
authors.forename: Tony
authors.initials: T
authors.lastname: Blick
authors.forename: John T
authors.initials: JT
authors.lastname: Price
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Pereira
authors.forename: Vijittra
authors.initials: V
authors.lastname: Leardkamonkarn
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000378:metabolism*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation
chemical_list: D024042:Collagen Type I; D039302:Integrin alphaVbeta3; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14