The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity

• Published in: International journal of cancer 2000-08, Vol.87 (3), p.336-342
• Main Authors: Morini, M, Mottolese, M, Ferrari, N, Ghiorzo, F, Buglioni, S, Mortarini, R, Noonan, D M, Natali, P G, Albini, A
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibodies, Monoclonal - pharmacology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Chemotaxis; Collagen - metabolism; Enzyme Induction; Extracellular Matrix Proteins - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Integrin alpha3beta1; Integrins - antagonists & inhibitors; Integrins - biosynthesis; Integrins - genetics; Integrins - immunology; Integrins - physiology; Ligands; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - physiology; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - immunology; Neoplasm Proteins - physiology; Phenotype; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Protease Inhibitors - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Thiophenes - pharmacology; Tumor Cells, Cultured
• ISSN: 0020-7136
• DOI: 10.1002/1097-0215(20000801)87:3<336::AID-IJC5>3.3.CO;2-V

The alpha 3 beta 1 integrin is elevated in several types of metastatic tumor and has been associated with increased migration and invasion. Our analysis of a series of mammary carcinomas of different histotypes and their corresponding metastases demonstrated significantly increased expression of alpha 3 beta 1 in the tumor metastases. We therefore studied alpha 3 beta 1 expression of several human breast carcinoma cell lines and its association with the invasive phenotype. The MDA-MB-231 cell line expressed high levels of the beta1, alpha 2, alpha 3, alpha 5, and alpha 6 integrin subunits along with moderate levels of the alpha v beta 3 integrin. This line was highly migratory and the most invasive using a chemo-invasion assay. In contrast, the other lines tested, MDA-MB-145, MCF-7, and SK-BR-3, showed lower migratory and invasive activity and reduced alpha 3 integrin subunit expression. Metalloproteases capable of degrading collagen IV are necessary for the invasive process. RT-PCR showed that MDA-MB-231 cells expressed MMP-9, but not MMP-2, gelatinase/collagenase IV. Gelatin zymography demonstrated that invading MDA-MB-231 cells released high levels of MMP-9 gelatinase activity. A direct role for this gelatinase in MDA-MB-231 cell invasion was confirmed by inhibition of invasion using the metalloprotease inhibitor Batimastat. Treatment of MDA-MB-231 cells with a function-blocking anti-alpha 3 antibody strongly inhibited migration and invasion. This correlated with a marked reduction in MMP-9 activity produced by MDA-MB-231 cells, suggesting a role for alpha 3 beta 1 ligand binding in cell signaling and regulation of extracellular matrix degradation.