α1 and α2 integrins mediate invasive activity of mouse mammary carcinoma cells through regulation of stromelysin-1 expression

Tumor cell invasion relies on cell migration and extracellular matrix proteolysis. We investigated the contribution of different integrins to the invasive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits alpha 6 and beta 1, but not against alpha 1 and alpha 2, inhibited cell locomotion on a reconstituted basement membrane in two-dimensional cell migration assays, whereas antibodies against beta 1, but not against a6 or alpha 2, interfered with cell adhesion to basement membrane constituents. Blocking antibodies against alpha 1 integrins impaired only cell adhesion to type ni collagen. Antibodies against alpha 1, alpha 2, alpha 6, and beta 1, but not alpha 5, integrin subunits reduced invasion of a reconstituted basement membrane. Integrins alpha 1 and alpha 2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antibodies against alpha 1 and alpha 2, but not alpha 6 and beta 1, integrin subunits inhibited both transcription and protein expression of the matrix metalloproteinase stromelysin-l. Inhibition of tumor cell invasion by antibodies against alpha 1 and alpha 2 was reversed by addition of recombinant stromelysin-l. In contrast, stromelysin-l could not rescue invasion inhibited by anti-alpha 6 antibodies. Our data indicate that alpha 1 and alpha 2 integrins confer invasive behavior by regulating stromelysin-1 expression, whereas alpha 6 integrins regulate cell motility. These results provide new insights into the specific functions of integrins during tumor cell invasion.