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Two different RXR agonists (Targretin and UAB 30), lipitor, and rosiglitazone were examined for their ability to inhibit the formation of ER negative mammary cancers in MMTV-Neu transgenic mice. The rexinoid Targretin (which is clinically employed in the treatment of cutaneous lymphoma) increases serum triglycerides levels, while UAB-30 does not. MMTV-Neu female mice were initially treated with dimethybenzanthracene (DMBA), 1.0 mg/mouse/week, by gavage for 4 weeks. Beginning five days after the last DMBA treatment, diets were supplemented either with targretin (250 mg/kg diet) or UAB-30 (300 mg/kg diet). At 105 days after the last DMBA treatment, Targretin and UAB-30 reduced the multiplicity of mammary cancers by 72 and 61%, respectively (controls had a multiplicity of 5.7 cancers/mouse). In addition, the preventive efficacy of Targretin (250 mg/kg diet), initiated either early (10 weeks of age) or late (24 weeks of age), was evaluated in female mice that were heterozygous both for MMTV-Neu and KO of the p53 tumor suppressor gene. Treatment with Targretin early or late reduced mammary cancer incidence by 46 and 16% and cancer multiplicity by 69 and 56%, respectively. In contrast, Targretin failed to inhibit the formation of lymphomas or sarcomas which also arise in these bitransgenic mice. Lipitor and rosiglitazone were also evaluated in a MMTV-Neu; P53 KO bitransgenic mouse model. Preliminary studies with either agent have shown minimal activity in the prevention of ER- mammary tumors in these bitransgenic mice. (Supported by NCI contract HHSN261200433001C)

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA