The retinoid X receptor-selective retinoid, LGD1069, down-regulates cyclooxygenase-2 expression in human breast cells through transcription factor crosstalk: implications for molecular-based chemoprevention.
Retinoids and their derivatives can suppress the development of cancer in animals and in humans. We and others have shown that retinoid X receptor (RXR)-selective retinoids or "rexinoids" suppress the development of breast cancer in several animal models with minimal toxicity. LGD1069 (Bexarotene) is a potent RXR-selective retinoid with reduced toxicity compared with naturally occurring retinoids. In this study, we investigated the expression of LGD1069-modulated biomarkers. We previously did cDNA array analysis of LGD1069-treated breast cells using Affymetrix microarrays. These studies identified many LGD1069-regulated genes, one of which was cyclooxygenase-2 (COX-2). Because COX-2 inhibitors have been shown to prevent cancer in other model systems, we investigated whether LGD1069 inhibits the expression of COX-2 in mammary tissue and in normal human mammary epithelial cells (HMEC). In mouse mammary tumor virus-erbB2 mice treated with LGD1069, there was a marked decrease of COX-2 expression in both normal and malignant mammary tissues. The effect of LGD1069 on COX-2 expression was also investigated in normal human breast cells. COX-2 expression was markedly reduced by treatment with LGD1069 at the RNA and protein level in normal HMECs; LGD1069 suppressed COX-2 promoter activity. We also showed that LGD1069 inhibited activator protein (AP-1)-dependent transcription in these breast cells, and that suppression of COX-2 expression was due to sequestration of CBP/p300. These results from in vivo and in vitro studies suggest that LGD1069, an RXR-selective retinoid, inhibits COX-2 expression by suppression of COX-2 transcription in part through transrepression of the AP-1 transcription factor. Thus, RXR-selective retinoids that inhibit AP-1 activity and suppress COX-2 expression may be particularly promising drugs for breast cancer prevention. Furthermore, such RXR-selective retinoids may be most useful in combination with antiestrogens for more effective prevention of breast cancer in women at high risk of this disease.
Kong
Gu
G
Breast Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Kim
Hee-Tae
HT
Wu
Kendall
K
DeNardo
David
D
Hilsenbeck
Susan G
SG
Xu
Xiao-Chun
XC
Lamph
William W
WW
Bissonnette
Reid
R
Dannenberg
Andrew J
AJ
Brown
Powel H
PH
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000077610:Bexarotene; D001940:Breast / Q000187:drug effects* / Q000201:enzymology; D001943:Breast Neoplasms / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D050881:E1A-Associated p300 Protein; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D047488:Retinoid X Receptors / Q000378:metabolism*; D013379:Substrate Specificity; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D016588:Anticarcinogenic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D000077610:Bexarotene; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse