title: Involvement of insulin-like growth factor binding protein-3 in peroxisome proliferator-activated receptor gamma-mediated inhibition of breast cancer cell growth.
abstract: We have previously reported that insulin-like growth factor binding protein-3 (IGFBP-3), a protein with dichotomous effects on both cell proliferation and cell survival, interacts with peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits adipogenic PPARγ signaling. We now show that IGFBP-3 and PPARγ interact in breast cancer cells, through amino- and carboxyl-terminal residues of IGFBP-3. IGFBP-3 and the PPARγ ligands, rosiglitazone or 15-deoxy-Δ(12,14)-prostaglandin J2, separately inhibited the proliferation of MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells. However, growth inhibition by IGFBP-3 and PPARγ ligand combined was greater than by either alone. Two IGFBP-3 mutants with reduced PPARγ binding caused no growth inhibition when used alone and abolished the inhibitory effect of rosiglitazone when used in combination with PPARγ ligand. Cell growth inhibition by PPARγ ligands was substantially blocked by IGFBP-3 siRNA and restored by exogenous IGFBP-3. We conclude that the interaction between IGFBP-3 and PPARγ is important for the growth-inhibitory effect of PPARγ ligands in human breast cancer cells, suggesting that IGFBP-3 expression by breast tumors may regulate their sensitivity toward PPARγ ligands.
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Cindy K
authors.initials: CK
authors.lastname: Pon
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Sue M
authors.initials: SM
authors.lastname: Firth
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Electronic address: robert.baxter@sydney.edu.au.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Baxter
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D009363:Neoplasm Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Breast cancer; IGFBP-3; Nuclear hormone receptor; PPARγ