Ligands for peroxisome proliferator-activated receptorγ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells <i>in vitro</i> and in BNX mice

TLDR

Ligand activation of nuclear hormone receptors such as PPARγ and retinoic acid receptors induces differentiation, apoptosis, and growth inhibition in breast cancer cells, with PPARγ expressed in these cells and its synthetic agonist troglitazone shown to suppress proliferation and promote lipid accumulation. The apoptosis induced by troglitazone and all‑trans‑retinoic acid is driven by down‑regulation of BCL‑2, as forced BCL‑2 over‑expression blocks cell death. Troglitazone alone reversibly inhibits MCF7 clonal growth, while its combination with ATRA synergistically and irreversibly suppresses proliferation, induces apoptosis, reduces BCL‑2, and in mouse xenografts causes tumor regression and fibrosis without toxicity, suggesting a selective, nontoxic therapy for breast cancer.

Abstract

Induction of differentiation and apoptosis in cancer cells through ligands of nuclear hormone receptors (NHRs) is a novel and promising approach to cancer therapy. All- trans -retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor γ (PPARγ) is expressed in breast cancer cells. Activation of PPARγ through a synthetic ligand, troglitazone (TGZ), and other PPARγ-activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10 −5 M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10 −5 M) and ATRA (10 −6 M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.