Invasion and
metastasis are the main causes of death in
breast cancer patients. Increased expression of
matrix metalloproteinases (
MMPs), especially
gelatinases (MMP-2 and -9), has been closely associated with
tumor progression. One of the
nuclear hormone receptors (NHR),
peroxisome proliferator-activated receptor gamma (
PPARgamma), is a
ligand-activated transcriptional factor that regulates cell proliferation, differentiation and apoptosis in both normal and
cancer cells. Recent data indicate that
PPARgamma activation by its
ligands can also lead to the inhibition of
gelatinase B (MMP-9) and the blockage of migration in macrophages and muscle cells, implying the possibility that
PPARgamma ligands may possess anti-invasive activities on
tumor cells. In this study, we showed that treatment of the highly aggressive human
breast cancer cell line MDA-MB-231 with the synthetic
PPARgamma ligands pioglitazone (PGZ),
rosiglitazone (RGZ),
GW7845 or its natural
ligand 15-deoxy-delta 12, 14-prostaglandin J2(15d-PGJ2), at concentrations at which no obvious cytotoxicity was observed in vitro, led to a significant inhibition of the invasive capacities of this cell line through a reconstituted basement membrane (
Matrigel) in a Transwell chamber model.
All-trans-retinoic acid (ATRA), a
ligand for
retinoic acid receptor (RAR), was also studied and showed a similar inhibitory effect on invasion. Although no change was observed in the expression of MMP-9 after challenge with
PPARgamma ligands and/or ATRA on this cell line, the natural tissue inhibitor of
gelatinases, namely the tissue inhibitor of
MMP 1 (TIMP-1) was upregulated by these treatments and the gelatinolytic activities of
gelatinases in the
conditioned media were decreased. Since MMP-2 was not detectable in the
conditioned media of MDA-MB-231 cells, and the gelatinolytic activities of the
conditioned media were reduced only by MMP-9
neutralizing antibodies, it is most likely that the reduction of gelatinolytic activities by
PPARgamma ligands and/or ATRA was due to the decrease of MMP-9 activities. Because MMP-9 was absolutely required in the transmigration of this cell line through
Matrigel in our in vitro model as demonstrated by
neutralizing antibodies against MMP-2 and -9, we concluded that down-regulation of
gelatinase activities is, at least in part, responsible for the reduction of the invasive capacities of MDA-MB-231 cell line in vitro. Our results, for the first time, indicate that
PPARgamma ligands may have therapeutic value for the treatment of highly invasive
breast cancer by targeting its invasive behavior.