Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid

Powel H. Brown, Kotha Subbaramaiah, Amoi P. Salmon, Rebecca Baker, Robert A. Newman, Peiying Yang, Xi Kathy Zhou, Reid P. Bissonnette, Andrew Dannenberg, Louise R. Howe

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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 combiningsubmaximal 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 drugindividually. 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 modulatingeicosanoid 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.

Original languageEnglish (US)
Pages (from-to)208-214
Number of pages7
JournalCancer Prevention Research
Volume1
Issue number3
DOIs
StatePublished - Aug 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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