maspin suppresses the invasive phenotype of human breast carcinoma

The recently discovered tumor suppressor gene maspin has been shown to inhi bit tumor cell motility, invasion, and metastasis in breast cancer by our l aboratories, Nonetheless, the exploitation of maspin as a potential diagnos tic and/or therapeutic tool has remained limited due to the lack of knowled ge concerning its molecular and biological mechanism(s) of action. The work reported here demonstrates that recombinant maspin (rMaspin) has the abili ty to induce higher cell surface levels of alpha(5)- and alpha(3)-containin g integrins and reduced levels of alpha(2)-, alpha(4)-, alpha(6)-, alpha(v) -, and some beta(1)-containing integrins in the metastatic human breast car cinoma cell line MDA-MB-435 concomitant with its ability to inhibit the inv asive process in vitro. Furthermore, treatment of MDA-MB-435 cells with rMa spin results in the selective adhesion of the cell to a fibronectin matrix and conversion from a fibroblastic to a more epithelial-like phenotype, In addition, the ability of rMaspin to inhibit the invasive process can be abr ogated with a blocking antibody to the alpha(5)beta(1) integrin, which dimi nishes the ability of the cells to invade through a fibronectin matrix-cont aining barrier in vitro, Taken together, these data address the hypothesis that rMaspin reduces the invasive phenotype of MDA-MB-435 cells by altering their integrin profile, particularly alpha(5), which in turn converts thes e cells to a more Benign epithelial phenotype, with less invasive ability. These data pro,ide new insights into the biological significance of this tu mor suppressor gene found in normal mammary epithelium and may form the bas is of novel therapeutic strategies in the management of breast carcinoma.