Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells

A serpin was identified in normal mammary gland by differential cDNA sequen cing. In situ hybridization has detected this serpin exclusively in the myo epithelial cells on the normal and noninvasive mammary epithelial side of t he basement membrane and thus was named myoepithelium-derived serine protei nase inhibitor (MEPI), No MEPI expression was detected in the malignant bre ast carcinomas. MEPI encodes a 405-aa precursor, including an 18-residue se cretion signal with a calculated molecular mass of 46 kDa, The predicted se quence of the new protein shares 33% sequence identity and 58% sequence sim ilarity to plasminogen activator inhibitor (PAI) I and PAI-2. To determine whether MEPI can modulate the in vivo growth and progression of human breas t cancers, we transfected a full-length MEPI cDNA into human breast cancer cells and studied the orthotopic growth of MEPI-transfected vs. control clo nes in the mammary fat pad of athymic nude mice. Overexpression of MEPI inh ibited the invasion of the tells in the in vitro invasion assay. When injec ted orthotopically into nude mice, the primary tumor volumes, axillary lymp h node metastasis, and lung metastasis were significantly inhibited in MEPI -transfected clones as compared with controls. The expression of MEPI in my oepithelial cells may prevent breast cancer malignant progression leading t o metastasis.