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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.

Abstract
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.
AuthorsGu Kong, Hee-Tae Kim, Kendall Wu, David DeNardo, Susan G Hilsenbeck, Xiao-Chun Xu, William W Lamph, Reid Bissonnette, Andrew J Dannenberg, Powel H Brown
JournalCancer research (Cancer Res) Vol. 65 Issue 8 Pg. 3462-9 (Apr 15 2005) ISSN: 0008-5472 [Print] United States
PMID15833882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Anticarcinogenic Agents
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Membrane Proteins
  • Nuclear Proteins
  • Retinoid X Receptors
  • Tetrahydronaphthalenes
  • Trans-Activators
  • Transcription Factor AP-1
  • Bexarotene
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
Topics
  • Animals
  • Anticarcinogenic Agents (pharmacology)
  • Bexarotene
  • Breast (drug effects, enzymology)
  • Breast Neoplasms (prevention & control)
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors (pharmacology)
  • Down-Regulation (drug effects)
  • E1A-Associated p300 Protein
  • Female
  • Humans
  • Mammary Neoplasms, Experimental (drug therapy, enzymology, genetics)
  • Membrane Proteins
  • Mice
  • Nuclear Proteins (antagonists & inhibitors, metabolism)
  • Promoter Regions, Genetic (drug effects)
  • Prostaglandin-Endoperoxide Synthases (biosynthesis, genetics)
  • Retinoid X Receptors (metabolism)
  • Substrate Specificity
  • Tetrahydronaphthalenes (pharmacology)
  • Trans-Activators (antagonists & inhibitors, metabolism)
  • Transcription Factor AP-1 (antagonists & inhibitors, metabolism)
  • Transcriptional Activation (drug effects)
  • Transfection

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