Identifying the Molecular Mechanism of Tumor Suppression by Maspin in Breast Cancer

摘要

Maspin is a unique member of the serpin family that shares extensive homology with monocyte-neutrophil elastase inhibitor, PM-2 and other serpins. Initially identified as a class II tumor suppressor gene, maspin has been shown to inhibit invasion and motility of mammary tumors. When maspin gene was introduced into breast tumor cells, it was demonstrated that tumor transfectants expressing maspin exhibited significant decrease in breast tumor growth and metastasis in nude mice. Maspin gene expressipn is not detected in most breast tumors and loss of its expression is correlated with tumor invasiveness. Maspin also found to be a potent angiogenesis inhibitor. Based on the previous work by my laboratory and other colleague, I hypothesize that maspin possesses multiple functionality that requires its interaction with multiple target proteins. Extracellular maspin may bind to the cell surface and regulate cell adhesion through integrin signal pathway. Maspin could act intracellularly or be secreted to act in a paracrine fashion on adjacent cells. I propose to isolate maspin target(s) by combined genetic and biochemical approaches. Once the maspin targets are identified, deletion and mutagenesis studies will be carried out to identify the functional domain of maspin that is responsible for such protein-protein interaction.