title: The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells.
abstract: 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 (PPARgamma) affects pathways important in a variety of human diseases. Here we show that the activation of PPARgamma through the 15-deoxy-Delta-12,14-prostaglandin J(2) (PG-J(2)) 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-J(2) 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-J(2). Furthermore, PG-J(2) can abolish the NRG1 and NRG2-induced increase in anchorage-independent growth of these cells. PG-J(2) 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-J(2) on the activity of the ErbB receptors in breast cancer cells.
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma, 28029-Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pignatelli
authors.forename: M
authors.initials: M
authors.lastname: Cortés-Canteli
authors.forename: C
authors.initials: C
authors.lastname: Lai
authors.forename: A
authors.initials: A
authors.lastname: Santos
authors.forename: A
authors.initials: A
authors.lastname: Perez-Castillo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D002455:Cell Division / Q000502:physiology; D002469:Cell Separation; D003114:Colony-Forming Units Assay; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D020880:Neuregulins / Q000378:metabolism*; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D007155:Immunologic Factors; D020880:Neuregulins; D018739:Oncogene Proteins v-erbB; D015230:Prostaglandin D2; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D017526:Receptor, IGF Type 1; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C097240:15-deoxy-delta(12,14)-prostaglandin J2