LIGANDS FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND RETINOIC ACID RECEPTOR INHIBIT GROWTH AND INDUCE APOPTOSIS OF HUMAN BREAST-CANCER CELLS IN-VITRO AND IN BNX MICE

Induction of differentiation and apoptosis in cancer cells through lig ands of nuclear hormone receptors (NHRs) is a novel and promising appr oach to cancer therapy. All-trans-retinoic acid (ATRA), an RA receptor -specific NHR ligand, is now used for selective cancers. The NHR, pero xisome proliferator-activated receptor gamma (PPAR gamma) is expressed in breast cancer cells. Activation of PPAR gamma through a synthetic ligand, troglitazone (TGZ), and other PPAR gamma-activators cause inhi bition of proliferation and lipid accumulation in cultured breast canc er 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 ATR A (10(-6) M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrea se of their bcl-2 protein levels. Similar effects are noted with in vi tro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and AT RA may be related to the striking down-regulation of bcl-2, because fo rced 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 AT RA causes prominent apoptosis and fibrosis of these tumors without tox ic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.