Abstract
Abstract Tumor cell migration is a complex event mediated by the genetic characteristics of the tumor cells themselves in cooperation with changes in the tissue microenvironment. ADAM9, a member of a family of transmembrane matrix-metalloproteases named for their integrin-binding Disintegrin And Metalloprotease domains, is implicated in cell-cell and cell-matrix interactions as well as in shedding of receptors and ligands. ADAM9 is present in breast cancer tumors and cell lines as two alternatively spliced isoforms—ADAM9-L and the truncated, secreted, ADAM9-S. We find that ADAM9-S is expressed primarily in the more migratory basal subtype of breast cancer cell lines, and exogenous and endogenous overexpression of ADAM9-S increases breast cancer cell migration, leading to our hypothesis that ADAM9 present in the breast tumor environment mediates tumor cell migration. Using lentiviral-shRNA constructs, we silenced expression of endogenous human ADAM9 protein in the BT549, ZR75-1 and CAMA-1 breast cancer cell lines, resulting in an increase in cell migration measured by transwell assay. This enhanced migration is reversed by reintroduction of ADAM9-L protein into these cells, while reintroduction of ADAM9-S enhances this migration phenotype in a metalloprotease-dependent manner, showing opposing roles for the two isoforms of ADAM9 in breast cancer cell migration. Furthermore, analysis of functional domain mutants of ADAM9-L shows that ADAM9-L suppresses cell migration in a metalloprotease-independent manner. We also find that ADAM9-L expression alters the migratory phenotype of α-6 integrin-blocking antibody GOH-indicating a role for ADAM9-L in integrin signaling. Future analysis of the proteolytic substrates of ADAM9-S, as well as the subcellular localization and downstream signaling of ADAM9-will further illuminate the mechanisms by which ADAM9 isoforms differentially mediate cell migration. Citation Information: Cancer Res 2009;69(23 Suppl):B8.
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