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Combination Chemoprevention of HER2/neu-Induced Breast Cancer Using a Cyclooxygenase-2 Inhibitor and a Retinoid X Receptor–Selective Retinoid

Authors' Affiliations: ¹ Breast Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; ² Departments of Medicine, ³ Cell and Developmental Biology, and ⁴ Public Health, Weill Medical College of Cornell University; ⁵ Strang Cancer Research Laboratory, Rockefeller University, New York, New York; ⁶ Pharmaceutical Development Center, M. D. Anderson Cancer Center, Houston, Texas; and ⁷ Department of Molecular Oncology, Ligand Pharmaceuticals, Inc., San Diego, California

Requests for reprints: Louise R. Howe, Department of Cell and Developmental Biology, Weill Cornell Medical College, Box 60, 1300 York Avenue, New York, NY 10065. Phone: 212-792-5174; Fax: 212-249-0013; E-mail: lrhowe@med.cornell.edu.

The inducible prostaglandin synthase isoform cyclooxygenase-2 (COX-2) is overexpressed in 40% of human breast carcinomas and in precancerous breast lesions, particularly in association with overexpression of human epidermal growth factor receptor 2 (HER2/neu). Experimental breast cancer can be suppressed by pharmacologic inhibition or genetic ablation of Cox-2, suggesting potential clinical utility of COX-2 inhibitors with respect to breast cancer. Importantly, several clinical trials have found reduced colorectal adenoma formation in individuals administered selective COX-2 inhibitors. However, such trials also identified increased cardiovascular risk associated with COX-2 inhibitor use. The goal of this research was to test whether improved chemopreventive efficacy could be achieved by combining submaximal doses of a selective COX-2 inhibitor and a retinoid X receptor–selective retinoid (rexinoid). The rate of HER2/neu-induced mammary tumor formation was substantially delayed by coadministration of the COX-2 inhibitor celecoxib (500 ppm in diet) and the rexinoid LGD1069 (10 mg/kg body weight; oral gavage) to MMTV/neu mice. Median time to tumor formation was increased from 304 to >600 days (P < 0.0001). The combination was substantially more effective than either drug individually. Similarly, potent suppression of aromatase activity was observed in mammary tissues from the combination cohort (44% of control; P < 0.001). Regulation of aromatase expression and activity by COX-derived prostaglandins is well established. Interestingly however, single agent LGD1069 significantly reduced mammary aromatase activity (71% of control; P < 0.001) without modulating eicosanoid levels. Our data show that simultaneous blockade of COX/prostaglandin signaling and retinoid X receptor–dependent transcription confers potent anticancer efficacy, suggesting a novel avenue for clinical evaluation.

Key Words: COX-2 • HER2/neu • RXR-selective retinoid

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