15d-PGJ2 inhibits NF-κB and AP-1-mediated MMP-9 expression and invasion of breast cancer cell by means of a heme oxygenase-1-dependent mechanism

Activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) serves as a key factor in the proliferation and invasion of breast cancer cells and is a potential therapeutic target for breast cancer. However, the mechanisms underlying this effect remain largely unknown. Herne oxygenase-1 (HO-1) is induced and over-expressed in various cancers and is associated with features of tumor aggressiveness. Recent studies have shown that HO-1 is a major downstream target of PPAR gamma. In this study, we investigated the effects of induction of HO-1 by PPAR gamma on TPA-induced MMP-9 expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-kappa B/AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ(2), a natural PPAR gamma ligand. 15d-PGJ(2) induced HO-1 expression in a dose-dependent manner. Interestingly, HO-1 siRNA significantly attenuated the inhibition of TPA-induced MMP-9 protein expression and cell invasion by 15d-PGJ(2). These results suggest that 15d-PGJ(2) inhibits TPA-induced MMP-9 expression and invasion of MCF-7 cells by means of a heme oxygenase-1-dependent mechanism. Therefore, PPAR gamma/HO-1 signaling-pathway inhibition may be beneficial for prevention and treatment of breast cancer.