BAG-1 inhibits PPARγ-induced cell death, but not PPARγ-induced transcription, cell cycle arrest or differentiation in breast cancer cells

Abstract

BAG-1 is a pleiotropic protein that exists as multiple isoforms. BAG-1 overexpression in breast cancer is associated with outcome. BAG-1 modulates the function of various nuclear hormone receptors, including the oestrogen receptor, and BAG-1 can influence the in vitro action of anti-hormonal therapies such as cyproterone acetate in prostate cancer. Activation of PPARgamma, a nuclear hormone receptor important for lipid and glucose homeostasis, may present a new therapeutic approach for breast cancer, since PPARgamma agonists promote cell cycle arrest, differentiation and apoptosis in breast cancer cells. Here we determined whether BAG-1 also modulated PPARgamma function in MCF7 cells. 15-deoxy-Delta12, 14-prostaglandin J(2) (15dPGJ2), an agonistic ligand for PPARgamma, induced expression of HSP70, a BAG-1 binding partner, but did not alter BAG-1 isoform expression. Overexpression of BAG-1 isoforms did not alter PPARgamma-dependent transcription or interfere with 15dPGJ2-induced cell cycle arrest or differentiation. However, overexpression of BAG-1 isoforms did interfere with induction of cell death by 15dPGJ2. Thus, BAG-1 is unlikely to directly modulate PPARgamma function, but the overexpression of BAG-1 in some breast cancers may limit the efficacy of PPARgamma agonists as cancer therapies, by suppression of PPARgamma-induced cell death pathways.