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Journal of Cell Science 114, 4117-4126 (2001)
© 2001 The Company of Biologists Limited

RESEARCH ARTICLE

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

Miguel Pignatelli1, Marta Cortés-Canteli1, Cary Lai2, Angel Santos3,* and Ana Perez-Castillo1,*

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 {gamma} isoform (PPAR{gamma}) affects pathways important in a variety of human diseases. Here we show that the activation of PPAR{gamma} through the 15-deoxy-{Delta}-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{gamma}, Transformation


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© The Company of Biologists Ltd 2001