alpha 1 and alpha 2 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 prote olysis. We investigated the contribution of different integrins to the inva sive activity of mouse mammary carcinoma cells. Antibodies against integrin subunits alpha 6 and beta 1, but not against alpha 1 and alpha 2, inhibite d cell locomotion on a reconstituted basement membrane in two-dimensional c ell migration assays, whereas antibodies against beta 1, but not against a6 or alpha 2, interfered with cell adhesion to basement membrane constituent s. Blocking antibodies against alpha 1 integrins impaired only cell adhesio n to type ni collagen. Antibodies against alpha 1, alpha 2, alpha 6, and be ta 1, but not alpha 5, integrin subunits reduced invasion of a reconstitute d basement membrane. Integrins alpha 1 and alpha 2, which contributed only marginally to motility and adhesion, regulated proteinase production. Antib odies against alpha 1 and alpha 2, but not alpha 6 and beta 1, integrin sub units inhibited both transcription and protein expression of the matrix met alloproteinase stromelysin-l. Inhibition of tumor cell invasion by antibodi es against alpha 1 and alpha 2 was reversed by addition of recombinant stro melysin-l. In contrast, stromelysin-l could not rescue invasion inhibited b y anti-alpha 6 antibodies. Our data indicate that alpha 1 and alpha 2 integ rins confer invasive behavior by regulating stromelysin-1 expression, where as alpha 6 integrins regulate cell motility. These results provide new insi ghts into the specific functions of integrins during tumor cell invasion.