Involvement of insulin-like growth factor binding protein-3 in peroxisome proliferator-activated receptor gamma-mediated inhibition of breast cancer cell growth

• IGFBP3 and PPARγ interact to inhibit breast cancer cell growth.
• Downregulation of IGFBP-3 reverses the inhibitory effect of PPARγ ligands.
• IGFBP-3 mutants with deficient PPARγ binding block the inhibitory effect of PPARγ ligands.
• IGFBP-3 expression by breast tumors may sensitize them to inhibition by PPARγ ligands

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-Δ12,14-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.