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[Cancer Research 63, 5926-5939, September 15, 2003]
© 2003 American Association for Cancer Research

Regular Articles

Activation of Peroxisome Proliferator-activated Receptor {gamma} by a Novel Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid Induces Growth Arrest and Apoptosis in Breast Cancer Cells1

Helene Lapillonne2, Marina Konopleva2, Twee Tsao, David Gold, Teresa McQueen, Robert L. Sutherland, Timothy Madden and Michael Andreeff3

Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy [H. L., M. K., T. T., T. Mc., M. A.], Department of Bioinformatics [D. G.], and Department of Pharmacology [T. Ma.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, and Cancer Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, Sydney, NSW 2010 Australia [R. L. S.]

Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is a member of the nuclear hormonal receptor superfamily expressed in a large number of human cancers. Here, we demonstrate that PPAR{gamma} is expressed and transcriptionally active in breast cancer cells independent of their p53, estrogen receptor, or human epidermal growth factor receptor 2 status. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a novel synthetic triterpenoid, is a ligand for PPAR{gamma}. We investigated the molecular mechanisms of CDDO on proliferation and apoptosis in breast cancer cells. In all breast cancer cell lines studied, CDDO transactivated PPAR{gamma}, induced dose- and time-dependent cell growth inhibition, cell cycle arrest in G1-S and G2-M, and apoptosis. We then used differential cDNA array analysis to investigate the molecular changes induced by CDDO. After 16-h exposure of MCF-7 and MDA-MB-435 cells to CDDO, we found genes encoding the following proteins to be up-regulated in both cell lines: p21Waf1/CIP1; GADD153; CAAT/enhancer binding protein transcription factor family members; and proteins involved in the ubiquitin-proteasome pathway. Among the down-regulated genes, we focused on the genes encoding cyclin D1, proliferating cell nuclear antigen, and the insulin receptor substrate 1. Using Western blot analysis and/or real-time PCR, we confirmed that CDDO regulated the expression of cyclin D1, p21Waf1/CIP1, and Bcl-2. Cyclin D1 and p21Waf1/CIP1 were additionally confirmed as important mediators of CDDO growth inhibition in genetically modified breast cancer cell lines. CDDO was able to significantly reduce the growth of MDA-MB-435 tumor cells in immunodeficient mice in vivo. The finding that CDDO can target genes critical for the regulation of cell cycle, apoptosis, and breast carcinogenesis suggests usage of CDDO as novel targeted therapy in breast cancer.




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