This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, K. Articles by Brown, P. H. Search for Related Content PubMed PubMed Citation Articles by Wu, K. Articles by Brown, P. H.

Suppression of Mammary Tumorigenesis in Transgenic Mice by the RXR-selective Retinoid, LGD1069¹

Breast Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 [K. W., H-T. K., S. G. H., S. K. M., P. H. B.]; Departments of Medicine [J. L. R.] and Pharmacology [J. G. K.], The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284; Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 [X-C. X.]; Department of Retinoid Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121 [W. W. L.]; and Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892 [J. E. G.]

Retinoids have been used in the clinic for the prevention and treatment of human cancers. They regulate several cellular processes including growth, differentiation, and apoptosis. Previously, we demonstrated that a pan-agonist retinoid 9-cis retinoic acid was able to suppress mammary tumorigenesis in the C3(1)-SV40 T-antigen (Tag) transgenic mouse model. However, significant toxicity was seen with this naturally occurring retinoid. We hypothesized that the cancer preventive effects of retinoids could be dissected from the toxic effects by using receptor-selective retinoids. In this study, we used TTNPB, an retinoic acid receptor-selective retinoid, and LGD1069, an retinoid X receptor-selective retinoid, to preferentially activate retinoic acid receptors and retinoid X receptors. In vitro, both compounds were able to inhibit the growth of T47D breast cancer cells. We then determined whether these retinoids prevented mammary tumorigenesis. C3(1)-SV40 Tag mice were treated daily by gastric gavage with vehicle, two different doses of TTNPB (0.3 or 3.0 µg/kg), or two different doses of LGD1069 (10 or 100 mg/kg). Mice were treated from approximately 6–8 weeks to 7–8 months of age. Tumor size and number were measured twice each week, and toxicities were recorded daily. Our data show that LGD1069 suppresses mammary tumorigenesis in C3(1)-SV40 Tag transgenic mice with no observable toxicity, whereas TTNPB had a modest chemopreventive effect, yet was very toxic. Median time to tumor development was 129 days in vehicle-treated mice versus 156 days in mice treated with 100 mg/kg LGD1069 (P = 0.05). In addition, tumor multiplicity was reduced by 50% in mice treated with LGD1069 (2.9 for vehicle, 2.4 for 10 mg/kg LGD1069, and 1.4 for 100 mg/kg, P 0.03). TTNPB-treated mice showed a delayed median time to tumor development (131 days for vehicle versus 154 days for 3.0 µg/kg TTNPB; P 0.05), but no changes were seen in tumor multiplicity. However, toxicity (skin erythema, hair loss) was seen in all of the mice treated with TTNPB. These data demonstrate that receptor-selective retinoids suppress mammary tumorigenesis in transgenic mice and that preventive effects of retinoids can be separated from their toxicity, demonstrating that receptor-selective retinoids are promising agents for the prevention of breast cancer.

This article has been cited by other articles:

				L. R. Howe Rexinoids and Breast Cancer Prevention Clin. Cancer Res., October 15, 2007; 13(20): 5983 - 5987. [Full Text] [PDF]

				Y. Li, Y. Zhang, J. Hill, Q. Shen, H.-T. Kim, X. Xu, S. G. Hilsenbeck, R. P. Bissonnette, W. W. Lamph, and P. H. Brown The Rexinoid LG100268 Prevents the Development of Preinvasive and Invasive Estrogen Receptor Negative Tumors in MMTV-erbB2 Mice Clin. Cancer Res., October 15, 2007; 13(20): 6224 - 6231. [Abstract] [Full Text] [PDF]

				K. Liby, D. B. Royce, R. Risingsong, C. R. Williams, M. D. Wood, R. A. Chandraratna, and M. B. Sporn A New Rexinoid, NRX194204, Prevents Carcinogenesis in Both the Lung and Mammary Gland Clin. Cancer Res., October 15, 2007; 13(20): 6237 - 6243. [Abstract] [Full Text] [PDF]

				T. L. Horn, K. E. O. Torres, J. M. Naylor, M. J. Cwik, C. J. Detrisac, I. M. Kapetanovic, R. A. Lubet, J. A. Crowell, and D. L. McCormick Subchronic Toxicity and Toxicogenomic Evaluation of Tamoxifen Citrate + Bexarotene in Female Rats Toxicol. Sci., October 1, 2007; 99(2): 612 - 627. [Abstract] [Full Text] [PDF]

				P. Tooker, W.-C. Yen, S.-C. Ng, A. Negro-Vilar, and T. W. Hermann Bexarotene (LGD1069, Targretin), a Selective Retinoid X Receptor Agonist, Prevents and Reverses Gemcitabine Resistance in NSCLC Cells by Modulating Gene Amplification Cancer Res., May 1, 2007; 67(9): 4425 - 4433. [Abstract] [Full Text] [PDF]

				H.-T. Kim, G. Kong, D. DeNardo, Y. Li, I. Uray, S. Pal, S. Mohsin, S. G. Hilsenbeck, R. Bissonnette, W. W. Lamph, et al. Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays Cancer Res., December 15, 2006; 66(24): 12009 - 12018. [Abstract] [Full Text] [PDF]

				R. Govindan, J. Crowley, L. Schwartzberg, P. Kennedy, C. Williams, B. Ekstrand, A. Sandler, D. Jaunakais, V. Bolejack, and R. Ghalie Phase II Trial of Bexarotene Capsules in Patients With Advanced Non-Small-Cell Lung Cancer After Failure of Two or More Previous Therapies J. Clin. Oncol., October 20, 2006; 24(30): 4848 - 4854. [Abstract] [Full Text] [PDF]

				K. Liby, M. Rendi, N. Suh, D. B. Royce, R. Risingsong, C. R. Williams, W. Lamph, F. Labrie, S. Krajewski, X. Xu, et al. The Combination of the Rexinoid, LG100268, and a Selective Estrogen Receptor Modulator, Either Arzoxifene or Acolbifene, Synergizes in the Prevention and Treatment of Mammary Tumors in an Estrogen Receptor-Negative Model of Breast Cancer. Clin. Cancer Res., October 1, 2006; 12(19): 5902 - 5909. [Abstract] [Full Text] [PDF]

				S. Woditschka, J. D. Haag, J. L. Waller, D. M. Monson, A. A. Hitt, H. L. Brose, R. Hu, Y. Zheng, P. A. Watson, K. Kim, et al. Neu-Induced Retroviral Rat Mammary Carcinogenesis: A Novel Chemoprevention Model for Both Hormonally Responsive and Nonresponsive Mammary Carcinomas. Cancer Res., July 1, 2006; 66(13): 6884 - 6891. [Abstract] [Full Text] [PDF]

				C. J. Grubbs, R. A. Lubet, V. R. Atigadda, K. Christov, A. M. Deshpande, V. Tirmal, G. Xia, K. I. Bland, I. Eto, W. J. Brouillette, et al. Efficacy of new retinoids in the prevention of mammary cancers and correlations with short-term biomarkers Carcinogenesis, June 1, 2006; 27(6): 1232 - 1239. [Abstract] [Full Text] [PDF]

				S Zanardi, D Serrano, A Argusti, M Barile, M Puntoni, and A Decensi Clinical trials with retinoids for breast cancer chemoprevention. Endocr. Relat. Cancer, March 1, 2006; 13(1): 51 - 68. [Abstract] [Full Text] [PDF]

				B. Liu, K.-W. Lee, H. Li, L. Ma, G. L. Lin, R. A.S. Chandraratna, and P. Cohen Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo Clin. Cancer Res., July 1, 2005; 11(13): 4851 - 4856. [Abstract] [Full Text] [PDF]

				W.-C. Yen and W. W. Lamph The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma Mol. Cancer Ther., May 1, 2005; 4(5): 824 - 834. [Abstract] [Full Text] [PDF]

				G. Kong, H.-T. Kim, K. Wu, D. DeNardo, S. G. Hilsenbeck, X.-C. Xu, W. W. Lamph, R. Bissonnette, A. J. Dannenberg, and P. H. Brown 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 Cancer Res., April 15, 2005; 65(8): 3462 - 3469. [Abstract] [Full Text] [PDF]

				H. Srinivas, D. M. Juroske, S. Kalyankrishna, D. D. Cody, R. E. Price, X.-C. Xu, R. Narayanan, N. L. Weigel, and J. M. Kurie c-Jun N-Terminal Kinase Contributes to Aberrant Retinoid Signaling in Lung Cancer Cells by Phosphorylating and Inducing Proteasomal Degradation of Retinoic Acid Receptor {alpha} Mol. Cell. Biol., February 1, 2005; 25(3): 1054 - 1069. [Abstract] [Full Text] [PDF]

				W.-C. Yen, M. R. Corpuz, R. Y. Prudente, T. A. Cooke, R. P. Bissonnette, A. Negro-Vilar, and W. W. Lamph A Selective Retinoid X Receptor Agonist Bexarotene (Targretin) Prevents and Overcomes Acquired Paclitaxel (Taxol) Resistance in Human Non-Small Cell Lung Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8656 - 8664. [Abstract] [Full Text] [PDF]

				S. Balasubramanian, R. A.S. Chandraratna, and R. L. Eckert Suppression of human pancreatic cancer cell proliferation by AGN194204, an RXR-selective retinoid Carcinogenesis, August 1, 2004; 25(8): 1377 - 1385. [Abstract] [Full Text] [PDF]

				G. E. Mao, V. E. Reuter, C. Cordon-Cardo, G. Dalbagni, H. I. Scher, J. B. deKernion, Z.-F. Zhang, and J. Rao Decreased Retinoid X Receptor-{alpha} Protein Expression in Basal Cells Occurs in the Early Stage of Human Prostate Cancer Development Cancer Epidemiol. Biomarkers Prev., March 1, 2004; 13(3): 383 - 390. [Abstract] [Full Text] [PDF]

				C. Lu, C. Speers, Y. Zhang, X. Xu, J. Hill, E. Steinbis, J. Celestino, Q. Shen, H. Kim, S. Hilsenbeck, et al. Effect of Epidermal Growth Factor Receptor Inhibitor on Development of Estrogen Receptor-Negative Mammary Tumors J Natl Cancer Inst, December 17, 2003; 95(24): 1825 - 1833. [Abstract] [Full Text] [PDF]

				C. Kavanaugh and J. E. Green The Use of Genetically Altered Mice for Breast Cancer Prevention Studies J. Nutr., July 1, 2003; 133(7): 2404S - 2409. [Abstract] [Full Text] [PDF]

				K. Wu, Y. Zhang, X.-C. Xu, J. Hill, J. Celestino, H.-T. Kim, S. K. Mohsin, S. G. Hilsenbeck, W. W. Lamph, R. Bissonette, et al. The Retinoid X Receptor-Selective Retinoid, LGD1069, Prevents the Development of Estrogen Receptor-Negative Mammary Tumors in Transgenic Mice Cancer Res., November 15, 2002; 62(22): 6376 - 6380. [Abstract] [Full Text] [PDF]