The ability to activate pro-
matrix metalloproteinase (pro-MMP)-2 via membrane type-
MMP is a hallmark of human
breast cancer cell lines that show increased invasiveness, suggesting that MMP-2 contributes to human
breast cancer progression. To investigate this, we have stably transfected
pro-MMP-2 into the human
breast cancer cell line MDA-MB-231, which lacks MMP-2 expression but does express its cell surface activator, membrane type 1-MMP. Multiple clones were derived and shown to produce
pro-MMP-2 and to activate it in response to
concanavalin A. In vitro analysis showed that the pro-MMP-2-transfected clones exhibited an increased invasive potential in Boyden chamber and
Matrigel outgrowth assays, compared with the parental cells or those transfected with vector only. When inoculated into the mammary fat pad of nude mice, each of the MMP-2-tranfected clones grew faster than each of the vector controls tested. After intracardiac inoculation into nude mice, pro-MMP-2-transfected clones showed a significant increase in the incidence of
metastasis to brain, liver, bone, and kidney compared with the vector control clones but not lung. Increased
tumor burden was seen in the primary site and in lung
metastases, and a trend toward increased burden was seen in bone, however, no change was seen in brain, liver, or kidney. This data supports a role for MMP-2 in
breast cancer progression, both in the growth of primary
tumors and in their spread to distant organs. MMP-2 may be a useful target for
breast cancer therapy when refinement of
MMP inhibitors provides for
MMP-specific agents.