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Integrin Fibronectin Receptors in Matrix Metalloproteinase-1–Dependent Invasion by Breast Cancer and Mammary Epithelial Cells

Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan

Integrins contribute to progression in many cancers, including breast cancer. For example, the interaction of ₅ß₁ with plasma fibronectin causes the constitutive invasiveness of human prostate cancer cells. Inhibition of this process reduces tumorigenesis and prevents metastasis and recurrence. In this study, naturally serum-free basement membranes were used as invasion substrates. Immunoassays were used to compare the roles of ₅ß₁ and ₄ß₁ fibronectin receptors in regulating matrix metalloproteinase (MMP)-1–dependent invasion by human breast cancer and mammary epithelial cells. We found that a peptide consisting of fibronectin PHSRN sequence, Ac-PHSRN-NH₂, induces ₅ß₁-mediated invasion of basement membranes in vitro by human breast cancer and mammary epithelial cells. PHSRN-induced invasion requires interstitial collagenase MMP-1 activity and is suppressed by an equimolar concentration of a peptide consisting of the LDV sequence of the fibronectin connecting segment, Ac-LHGPEILDVPST-NH₂, in mammary epithelial cells, but not in breast cancer cells. This sequence interacts with ₄ß₁, an integrin that is often down-regulated in breast cancer cells. Immunoblotting shows that the PHSRN peptide stimulates MMP-1 production by serum-free human breast cancer and mammary epithelial cells and that the LDV peptide represses PHSRN-stimulated MMP-1 production only in mammary epithelial cells. Furthermore, PHSRN stimulates MMP-1 activity in breast cancer cells and mammary epithelial cells with a time course that closely parallels invasion induction. Thus, down-regulation of surface ₄ß₁ during oncogenic transformation may be crucial for establishment of the ₅ß₁-induced, MMP-1–dependent invasive phenotype of breast cancer cells.

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