The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells

One of the most interesting recent developments in the nuclear receptor fie ld has been the identification of natural and synthetic agonists of the per oxisome proliferator-activated receptor (PPAR) family, coupled with a growi ng recognition that the gamma isoform (PPAR gamma) affects pathways importa nt in a variety of human diseases. Here we show that the activation of PPAR gamma through the 15-deoxy-Delta -12,14-prostaglandin J(2) (PG-J(2)) ligan d causes a dramatic inhibition of ErbB-2 and ErbB-3 tyrosine phosphorylatio n caused by neuregulin 1 (NRG1) and neuregulin 2 (NRG2) in MCF-7 cells. Thi s effect is accompanied by a very efficient blocking of ErbBs effects upon proliferation, differentiation and cell death in these cells. Preincubation of MCF-7 cells with PG-J(2) before addition of NRG1 and NRG2 had a dramati c growth-suppressive effect accompanied by accumulation of cells in the G0/ G1 compartment of the cell cycle, and a marked increase in apoptosis. NRG1 and NRG2 induce G1 progression, which was associated with stimulation of th e phosphatidylinositol-3 kinase (PI 3-K) pathway, whereas survival was depe ndent on ERK1/ERK2 activation. Both pathways were inhibited by PG-J(2). Fur thermore, PG-J(2) can abolish the NRG1 and NRG2-induced increase in anchora ge-independent growth of these cells. PG-J(2) also blocks phosphorylation o f other receptor tyrosine kinases, such as IGF-IR, in MCF-7 cells, and supp ress proliferation of other breast cancer cell lines. In summary, our data show a specific inhibitory action of PG-J(2) on the activity of the ErbB re ceptors in breast cancer cells.