Activation of peroxisome proliferator-activated receptor ¥ã (PPAR¥ã) 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. Heme 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¥ã. In this study, we investigated the effects of induction of HO-1 by PPAR¥ã on 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced matrix metalloproteinase-9 (MMP-9) expression and cell invasion using MCF-7 breast cancer cells. TPA treatment increased NF-¥êB /AP-1 DNA binding as well as MMP-9 expression. These effects were significantly blocked by 15d-PGJ©ü, a natural PPAR¥ã ligand. 15d-PGJ©ü 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©ü. These results suggest that 15d-PGJ©ü inhibits TPA-induced MMP-9 expression and invasion of MCF-7 cells through a heme oxygenase-1-dependent mechanism. Therefore, PPAR¥ã/HO-1 signaling pathway inhibition may be beneficial for prevention and treatment of breast cancer.