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

¹ Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma, 28029-Madrid
² Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037
³ Departamento de Bioquímica y Biología Molecular, Facultad de.Medicina, Universidad Complutense, Madrid

*Authors for correspondence (aperez{at}iib.uam.es; piedras3{at}eucmax.sim.ucm.es)

Accepted July 31, 2001

One of the most interesting recent developments in the nuclear receptor field has been the identification of natural and synthetic agonists of the peroxisome proliferator-activated receptor (PPAR) family, coupled with a growing recognition that the isoform (PPAR) affects pathways important in a variety of human diseases. Here we show that the activation of PPAR through the 15-deoxy--12,14-prostaglandin J₂ (PG-J₂) ligand causes a dramatic inhibition of ErbB-2 and ErbB-3 tyrosine phosphorylation caused by neuregulin 1 (NRG1) and neuregulin 2 (NRG2) in MCF-7 cells. This 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-J₂ before addition of NRG1 and NRG2 had a dramatic 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 the phosphatidylinositol-3 kinase (PI 3-K) pathway, whereas survival was dependent on ERK1/ERK2 activation. Both pathways were inhibited by PG-J₂. Furthermore, PG-J₂ can abolish the NRG1 and NRG2-induced increase in anchorage-independent growth of these cells. PG-J₂ also blocks phosphorylation of other receptor tyrosine kinases, such as IGF-IR, in MCF-7 cells, and suppress proliferation of other breast cancer cell lines. In summary, our data show a specific inhibitory action of PG-J₂ on the activity of the ErbB receptors in breast cancer cells.

Key words: Breast cancer, ErbBs, Phosphorylation, PPAR, Transformation