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¹ Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, District of Columbia 20037, USA
² Department of Surgery, The Ohio State University, Columbus, Ohio 43210, USA
³ Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio 43210, USA
⁴ Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, Ohio 43210, USA
⁵ Department of Management Science, The George Washington University School of Business, Washington, District of Columbia 20037, USA

(Requests for offprints should be addressed to J J Pinzone who is now at The Ohio State University Medical Center, McCampbell Hall, Room 445C, 1581 Dodd Drive, Columbus, Ohio 43210, USA; Email: joseph.pinzone{at}osumc.edu)

A Pumfrey is now at Department of Biology, Seton Hall University, South Orange, New Jersey 07079, USA

Peroxisome proliferator-activated receptor- (PPAR) is a member of the nuclear hormone superfamily and has multiple endogenous and pharmacological ligands, including 15-deoxy- ^12,14-prostaglandin J₂ and two thiazolidinediones (TZD), rosiglitazone and pioglitazone, which are used clinically to treat type-2 diabetes mellitus. PPAR agonists regulate development, cellular growth and metabolism in various tissues and have been documented to decrease cellular proliferation and to induce apoptosis of various tumour phenotypes, including breast cancer. However, the full spectrum of anti-tumour effects occurs only at suprapharmacological doses. In this study, we investigated the mechanism of rosiglitazone-induced anti-tumour effects of MDA-MB-231 human breast cancer cells, and used that information to predict rosiglitazone-induced sensitization of breast cancer cells to the effects of other compounds. We first confirmed that 100 µM rosiglitazone, but not lower doses, decreases MDA-MB-231 cell viability in vitro. We then used microarray gene expression analysis to determine early rosiglitazone-induced gene expression changes after 4-h exposure, which included 1298 genes that we grouped into functional categories. We selectively confirmed rosiglitazone-mediated effects on expression of key regulators of breast cancer proliferation and apoptosis, including p53, p21 and Bax. Finally, we used this information to predict that rosiglitazone would sensitize MDA-MB-231 cells to the anti-tumour effects of CH11, which trimerizes Fas, as well as tumour necrosis factor-. Moreover, we used the confirmed array data to predict cooperative activity of rosiglitazone and R-roscovitine (CYC202), an inhibitor of multiple cyclin-dependent kinases. We conclude that microarray analysis can determine early TZD-modulated changes in gene expression that help to predict effective in vitro drug combinations.