Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid.
The inducible prostaglandin synthase isoform cyclooxygenase-2 (COX-2) is overexpressed in approximately 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.
Brown
Powel H
PH
Breast Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
Subbaramaiah
Kotha
K
Salmon
Amoi P
AP
Baker
Rebecca
R
Newman
Robert A
RA
Yang
Peiying
P
Zhou
Xi Kathy
XK
Bissonnette
Reid P
RP
Dannenberg
Andrew J
AJ
Howe
Louise R
LR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077610:Bexarotene; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000068579:Celecoxib; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D018890:Chemoprevention / Q000379:methods*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000008:administration & dosage*; D047488:Retinoid X Receptors / Q000819:agonists; D012176:Retinoids / Q000008:administration & dosage; D013379:Substrate Specificity / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*
D052246:Cyclooxygenase 2 Inhibitors; D015777:Eicosanoids; D011720:Pyrazoles; D047488:Retinoid X Receptors; D012176:Retinoids; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene; D000068579:Celecoxib