Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR gamma ligands. To evaluate the therapeutic potential of increased PPAR gamma signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR gamma in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR gamma potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR gamma signaling serves as a tumor promoter in the mammary gland.