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

Kong, Gu; Kim, Hee Tae; Wu, Kendall; DeNardo, David G.; Hilsenbeck, Susan G.; Xu, Xiao Chun; Lamph, William W.; Bissonnette, Reid P.; Dannenberg, Andrew J.; Brown, Powel H.

doi:10.1158/0008-5472.can-03-2912

Cited by 53 publications

(49 citation statements)

References 26 publications

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“…In situ hybridization A previously described method of nonradioactive in situ hybridization was used for detection of COX-2 expression (Khuri et al, 2001;Kong et al, 2005). The stained sections were reviewed in a manner similar to immunohistochemistry.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression

et al. 2005

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Benzo [a]pyrene diol epoxide (BPDE, a carcinogen present in tobacco smoke and environmental pollution) has been shown to suppress retinoic acid receptor-beta2 (RAR-b 2 ) and induce cyclooxygenase-2 (COX-2) expression. Restoration of RAR-b 2 inhibited growth and colony formation of esophageal cancer cells, which was correlated with COX-2 suppression. In this study, we investigated the molecular mechanisms for RAR-b 2 -mediated suppression of COX-2 expression using BPDE as a tool. We found that BPDE-induced COX-2 expression was through inhibition of RAR-b 2 and consequently, induction of epidermal growth factor receptor (EGFR), extracellular signal-regulated protein kinases 1/2 (Erk1/2) phosphorylation, and c-Jun expression. Esophageal cancer cells that do not express RAR-b 2 did not respond to BPDE for induction of COX-2. BPDE was also unable to induce COX-2 expression after RAR-b 2 expression was manipulated in these esophageal cancer cells. Furthermore, BPDE induced time-dependent methylation of RAR-b 2 gene promoter in esophageal cancer cells. Transfection of RAR-b 2 expression vector into esophageal cancer cells suppressed expression of EGFR, Erk1/2 phosphorylation, c-Jun, and COX-2. In addition, co-treatment of RAR-b 2 -positive cells with BPDE and the MEK1/2 inhibitor U0126 caused little change in c-Jun and COX-2 expression. This study demonstrated that BPDE-suppressed expression of RAR-b 2 results in COX-2 induction and restoration of RAR-b 2 expression reduces COX-2 protein in esophageal cancer cells, thereby further supporting our previous finding that RAR-b 2 plays an important role in suppressing esophageal carcinogenesis.

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Section: Immunohistochemistrymentioning

confidence: 99%

Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression

et al. 2005

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“…Importantly, rexinoids also exhibit preventative activity in ER-negative breast cancer experimental models, thus potentially tackling the emergence of ER-negative tumours observed in prevention trials of SERMs. In addition, rexinoids have been found to down-regulate COX-2 expression in normal mammary epithelial cells (Kong et al 2005). This finding appears of great relevance in view of the role of COX-2 in breast carcinogenesis (Dannenberg & Subbaramaiah 2003) and of the recent alerts on the risks related to the longterm use of COX-2 inhibitors in chemopreventive trials (Bresalier et al 2005, Solomon et al 2005.…”

Section: Discussionmentioning

confidence: 95%

“…It has been found that, in premalignant cells, rexinoids induce a G1 cell cycle block by inducing the expression of growth-inhibitory molecules, such as RAR-b and IGFBPs, and by suppressing the expression of growthstimulating molecules, such as cyclin D1 and COX-2 (Brown et al 2004). Kong et al (2005) have recently reported that bexarotene markedly reduces COX-2 expression in normal human mammary epithelial cells by suppression of COX-2 transcription, in part through transrepression of the AP-1 transcription factor. On the whole, these studies suggest that rexinoids are promising agents for the prevention of breast cancer and may be particularly useful in preventing the appearance of ER-negative breast tumours.…”

Section: Trials Of Novel Retinoidsmentioning

confidence: 99%

Clinical trials with retinoids for breast cancer chemoprevention

Zanardi¹,

Serrano²,

Argusti³

et al. 2006

Endocr Relat Cancer

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Retinoids have been studied as chemopreventive agents in clinical trials due to their established role in regulating cell growth, differentiation and apoptosis in preclinical models. Experimental evidence suggests that retinoids affect gene expression both directly, by activating and/or repressing specific genes, and indirectly, by interfering with different signal transduction pathways. Induction of apoptosis is a unique feature of fenretinide, the most widely studied retinoid in clinical trials on breast cancer chemoprevention due to its selective accumulation in breast tissue and to its favourable toxicological profile. In a phase III breast cancer prevention trial, fenretinide showed a durable trend to a reduction of second breast malignancies in premenopausal women. This pattern was associated with a favourable modulation of circulating IGF-I and its main binding protein (IGFbinding protein-3, IGFBP-3), which have been associated with breast cancer risk in premenopausal women in different prospective studies. In a subsequent biomarker study on premenopausal women who had participated in the phase III trial, high IGF-I and low IGFBP-3 baseline levels were found to predict second breast cancer risk, although the magnitude of their changes during treatment did not fulfil the requirements for suitable surrogate end-point biomarkers. In postmenopausal women, fenretinide did not reduce second breast cancer incidence, nor did it induce significant modulation of the IGF system. Similarly, fenretinide was not found to affect risk biomarkers significantly in early postmenopausal women on hormone replacement therapy, who are at increased risk of developing breast cancer. Biomarker studies of fenretinide alone or in combination with different nuclear receptor ligands are being conducted. In particular, clinical trials of fenretinide and tamoxifen have proved to be feasible, and this combination appears to be safe and well tolerated in high-risk women, especially when low-dose tamoxifen is employed. Novel retinoid X receptor-selective retinoids, or rexinoids, have been shown to suppress the development of breast cancer in several animal models with minimal toxicity, and are being intensively studied either alone or in combination with selective oestrogen receptor modulators, both in vitro and in vivo. The rexinoid, bexarotene, has recently been approved for the treatment of patients with cutaneous T-cell lymphoma, and a biomarker trial with bexarotene in women with high breast cancer risk is currently underway.

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“…One of the controversies that arise regarding Targretin is the possible mechanism of action of this agent. It has been reported that Targretin can reduce the expression of COX-2 protein in normal mammary epithelium and tumors (15). The implication is that inhibition of COX-2, although perhaps indirectly, may be a significant target.…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive efficacy of Targretin in rodent models of urinary bladder, colon/intestine, head and neck and mammary cancers

et al. 2012

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Abstract. The chemopreventive efficacy of Targretin was evaluated in various rodent cancer models. In the rat model of 4-hydroxybutyl(butyl)nitrosamine (OH-BBN)-induced urinary bladder cancer, it was found that Targretin administered in the diet (beginning one week after the last OH-BBN treatment) for 5.5 months increased the number and size of urinary bladder cancers. In the azoxymethane (AOM)-induced model of colon carcinogenesis (in which rats develop minimally invasive colonic cancers), Targretin was ineffective as a chemopreventive agent, decreasing neither tumor incidence nor multiplicity. Treatment of Min mice with Targretin for 45 days similarly failed to decrease the multiplicity of small intestinal tumors. Similarly, no preventive efficacy was noted for Targretin when the incidence of tumors in the head and neck model (squamous cell tongue tumors) induced by 4-nitroquinoline 1-oxide (4-NQO) were examined. In contrast, use of even a suboptimal dose of Targretin (40 ppm) in a sensitive breast cancer model [methylnitrosourea (MNU)-induced ER + mammary cancers] reduced cancer multiplicity by 60%. Finally, based on the hypothesis that Targretin may decrease the expression of COX-2, the effects of Targretin and COX inhibitors were compared in these models. There was minimal overlap of efficacy. That is, models which were relatively susceptible to NSAIDs or COX-2 inhibitors tended not to be sensitive to Targretin and vice versa. IntroductionThe RXR agonist Targretin interacts with a group of nuclear receptors designated RXR receptors which are present in most cells in the body. These RXR receptors can then interact with and form heterodimers with the widest range of nuclear receptors (PPAR, CAR, PXR, RARs, TXR and VDR) (1). The resulting heterodimers initiate the activation of a wide variety of genes. Because of the wide range of physiological changes induced by RXR agonists, it was initially anticipated that they would prove useful as a generalized cancer prevention strategy (2). This hope was further supported by the fact that the retinoids (all-trans-retinoic acid, 13-cis-retinoic acid) which bind to RARs and in turn form heterodimers with RXRs, are active against a number of cancers including acute promyelocytic leukemia and squamous cell cancers of both the head and neck and skin (3,4). However, this class of agents was limited by certain toxicities associated with RAR activation; including cutaneous toxicities. Early studies with the RXR agonist Targretin showed it to be highly active in a variety of cell lines in culture (5). Although in vivo experiments with this class of agents are more limited, Targretin and other RXR agonists have been shown to be highly effective in preventing both ER + and ER -mammary tumors in animal models (6,7). With respect to the ER positive tumors, Targretin proved to be not only a preventive agent but was a highly effective therapeutic agent as well (6). Our laboratory, and others, has subsequently found that Targretin is active in mouse models of lung adenocarcinomas (8),...

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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

Cited by 53 publications

References 26 publications

Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression

Induction of cyclooxygenase-2 by benzo[a]pyrene diol epoxide through inhibition of retinoic acid receptor-β2 expression

Clinical trials with retinoids for breast cancer chemoprevention

Chemopreventive efficacy of Targretin in rodent models of urinary bladder, colon/intestine, head and neck and mammary cancers

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