title: Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer.
abstract: Galectin-3 cleavage is related to progression of human breast and prostate cancer and is partly responsible for tumor growth, angiogenesis and apoptosis resistance in mouse models. A functional polymorphism in galectin-3 gene, determining its susceptibility to cleavage by matrix metalloproteinases (MMPs)-2/-9 is related to racial disparity in breast cancer incidence in Asian and Caucasian women. The purpose of our study is to evaluate (i) if cleavage of galectin-3 could be related to angiogenesis during the progression of human breast cancer, (ii) the role of cleaved galectin-3 in induction of angiogenesis and (iii) determination of the galectin-3 domain responsible for induction of angiogenic response. Galectin-3 null breast cancer cells BT-459 were transfected with either cleavable full-length galectin-3 or its fragmented peptides. Chemotaxis, chemoinvasion, heterotypic aggregation, epithelial-endothelial cell interactions and angiogenesis were compared to noncleavable galectin-3. BT-549-H(64) cells harboring cleavable galectin-3 exhibited increased chemotaxis, invasion and interactions with endothelial cells resulting in angiogenesis and 3D morphogenesis compared to BT-549-P(64) cells harboring noncleavable galectin-3. BT-549-H(64) cells induced increased migration and phosphorylation of focal adhesion kinase in migrating endothelial cells. Endothelial cells cocultured with BT-549 cells transfected with galectin-3 peptides indicate that amino acids 1-62 and 33-250 stimulate migration and morphogenesis of endothelial cells. Immunohistochemical analysis of blood vessel density and galectin-3 cleavage in a breast cancer progression tissue array support the in vitro findings. We conclude that the cleavage of the N terminus of galectin-3 followed by its release in the tumor microenvironment in part leads to breast cancer angiogenesis and progression.
authors.affiliation: Tumor Progression and Metastasis, Department of Pathology, School of Medicine, Wayne State University, Detroit, MI, USA.
authors.forename: Pratima
authors.initials: P
authors.lastname: Nangia-Makker
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Tirza
authors.initials: T
authors.lastname: Raz
authors.forename: Larry
authors.initials: L
authors.lastname: Tait
authors.forename: Vitaly
authors.initials: V
authors.lastname: Balan
authors.forename: Victor
authors.initials: V
authors.lastname: Hogan
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D014162:Transfection
chemical_list: D037502:Galectin 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9