Cancer Prevention Research Combination Chemoprevention of HER2/neu-Induced Breast Cancer Using a Cyclooxygenase-2 Inhibitor and a Retinoid X Receptor–Selective Retinoid Powel H. Brown, 1 Kotha Subbaramaiah, 2 Amoi P. Salmon, 3,5 Rebecca Baker, 3,5 Robert A. Newman, 6 Peiying Yang, 6 Xi Kathy Zhou, 4 Reid P. Bissonnette, 7 Andrew J. Dannenberg 2 and Louise R. Howe 3,5 Abstract The inducible prostaglandin synthase isoform cyclooxygenase-2 (COX-2) is overex- pressed in ∼40% of human breast carcinomas and in precancerous breast lesions, particu- larly 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–se- lective 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 eico- sanoid levels. Our data show that simultaneous blockade of COX/prostaglandin signaling and retinoid X receptor–dependent transcription confers potent anticancer efficacy, sug- gesting a novel avenue for clinical evaluation. The inducible prostaglandin (PG) synthase cyclooxygenase-2 (COX-2) is strongly implicated in breast neoplasia (1, 2). COX-2 is overexpressed in ∼40% of human breast carcinomas and in 60% to 80% of preinvasive ductal carcinoma in situ lesions (1, 2). COX-2 overexpression in breast carcinomas correlates with poor prognosis and with several associated clinical vari- ables, including overexpression of human epidermal growth factor receptor 2 (HER2; also called neu and c-ERBB2; refs. 3–8). Epidemiologic data are broadly consistent with a protumori- genic role for COX enzymes. Several studies have identified reduced breast cancer incidence associated with the use of COX-inhibiting drugs including aspirin, nonsteroidal anti- inflammatory drugs, and selective COX-2 inhibitors (9–17). Consistent with the human expression data, Cox-2 is also up-regulated in rodent mammary tumors (18–22), and thus rodent breast cancer models have proved useful for analyz- ing the contribution of Cox-2 to mammary neoplasia. Nu- merous studies have shown that experimental breast cancer can be suppressed by inhibiting Cox activity using either conventional nonsteroidal antiinflammatory drugs or selective Cox-2 inhibitors (1, 2). Given the observed correla- tions between COX-2 and HER2/neu overexpression in hu- man breast tumors (3–6), HER2/neu-driven models are of particular interest. Both we and others have shown that HER2/neu-induced tumor formation is significantly delayed 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 Received 02/20/2008; accepted 02/27/2008. Grant support: NIH grants R03 CA105458 (L.R. Howe), R03 CA119273 (L.R. Howe), and R01 CA078480 (P.H. Brown); a Breast Cancer Alliance Young Inves- tigator Grant (L.R. Howe); the Breast Cancer Research Foundation (P.H. Brown and A.J. Dannenberg); and the Irving Weinstein Foundation, Inc. (L.R. Howe). Requests for reprints: Louise R. Howe, Department of Cell and Develop- mental 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. ©2008 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0021 208 Cancer Prev Res 2008;1(3) August 2008 www.aacrjournals.org Downloaded from http://aacrjournals.org/cancerpreventionresearch/article-pdf/1/3/208/2241668/08-0021.pdf by guest on 14 June 2022