Combination chemoprevention of HER2/neu-induced breast cancer using a COX-2 inhibitor and an RXR-selective retinoid Free

PR-6

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 genetic or pharmacological 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 have 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 days in control animals to >600 days in the celecoxib/LGD1069 group (P<0.0001). The combination was substantially more effective than either drug individually. Tumor multiplicity was also significantly reduced in the combination group relative to the control cohort (44% of control; P=0.027). Similarly, increased suppression of aromatase activity was observed in mammary tissues from the combination cohort relative to that achieved with either agent singly (44% of control; P<0.00001). 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<0.0001) without modulating eicosanoid levels. Our data demonstrate that together celecoxib and LGD1069 have potent anticancer efficacy, potentially worthy of clinical evaluation.