| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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.]
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
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. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Retinoids are vitamin A analogues, which function in regulating cell growth, differentiation, and apoptosis (7
, 8)
. They can bind to the nuclear retinoid receptors, i.e., RARs3
(
, ß, and 
) and RXRs (, ß, and ; Refs. 9
, 10
). These receptors bind to specific DNA sequences to regulate gene expression. The RAR and RXR family members are expressed differently during development and differentiation (11)
, and various isoforms of these proteins can heterodimerize to produce a variety of complexes to regulate different sets of retinoid-induced genes.
In vitro studies have shown that retinoids can inhibit the growth and invasion of cancer cells, and induce them to undergo apoptosis. Several laboratories, including ours, have found many different cancer cell lines to be growth inhibited by retinoids (12, 13, 14, 15) . The pan-agonist 9cRA has been found to inhibit proliferation, induce differentiation, and induce apoptosis in a variety of cell lines including the breast cancer cell line MCF-7 (15) . This retinoid binds both RARs and RXRs, and, thus, is able to activate both RAR- and RXR-dependent pathways.
9cRA has been shown to inhibit mammary carcinogenesis in the NMU-induced rat model (16) , and our previous studies have demonstrated that 9cRA suppresses mammary tumor development in a C3(1)-SV40 Tag transgenic mouse model (17) . These results have lead to use of 9cRA in humans for the treatment and prevention of cancer. However, in human clinical trials 9cRA has been found to have significant toxicity including skin changes, liver toxicity, cracking of the lips, and headaches (18) .
We hypothesized that receptor-selective retinoids could be used to separate the chemopreventive efficacy of retinoids from their toxic side effects. Thus, in this study we have investigated the ability of RAR- and RXR-selective retinoids to inhibit mammary tumorigenesis in the C3(1)-SV40 Tag mouse model, and have compared the side effects seen in animals treated with these retinoids. Our data demonstrate that the RAR-selective retinoid has modest chemopreventive activity, yet is highly toxic, whereas the RXR-selective retinoid, LGD1069, suppresses mammary tumorigenesis with no apparent side effects. These results demonstrate that chemopreventive efficacy of retinoids can be separated from toxicity using receptor-selective retinoids. The data support the development of RXR-selective retinoids for the prevention of human breast cancer.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Transient Transfections and Reporter Assays.
T47D breast cancer cells were transfected with 1–2 µg of plasmid DNA using FUGENE 6 (Roche). For 6 h, 10-6 M 9cRA, TTNPB, or LGD1069 were added to the cells followed by lysing the cells with a buffer containing 1 mM DTT, 100 mM potassium phosphate (pH 7.8), and 1% Triton X-100. Luciferase activity was assayed according to the luciferase assay kit protocol (Tropix, Inc., Bedford, MA). ß-Gal activity was determined by adding 20 µl of either diluted or undiluted cell lysate to 80 µl of ß-gal reagent buffer containing 88 mM phosphate buffer (pH 7.3), 11 mM KCl, 1 mM MgCl2, 54.7 µM ß-mercaptoethanol, and 4.4 mM ghlorophenol red-ß-D-galactopyranosisde (Roche) at 37°C, and the absorption at 600 nm was determined. Luciferase results were then normalized using the ß-gal assay results to control for transfection efficiency.
Growth Curve of T47D Breast Cancer Cells.
T47D breast cancer cells were treated with either 0.1% DMSO (control), 9cRA, TTNPB, or LGD1069 (retinoids at 10-6 M) for 8 days. Relative cell growth was measured using the CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay (Promega, Madison, WI). As described in the protocol, cells were incubated with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymehoxyphenyl)-2-(4-sulfphenyl)-2H-tetrazolium and phenazine methosulfate, and conversion into a formazan product was determined at 550 nm. Measurements of cell growth and medium changes were performed every other day.
Transgenic Mice.
Female C3(1)-SV40 Tag transgenic mice (obtained from the Animal Production Program, National Cancer Institute, Frederick, MD) were housed in the university animal facilities. These mice have been shown to develop mammary tumors by 6 months of age (19)
. Animals were obtained at 6–8 weeks of age and treated with retinoids daily for 7 days a week until the age of 7–8 months. Virgin animals were used because the development of mammary tumors does not depend on pregnancy. Animals were fed a controlled diet of Teklad LM-485 Mouse/Rat Diet (Harlan Teklad, Madison, WI).
Treatment and Data Collection.
TTNPB and LGD1069 were suspended in purified sesame oil (Croda, Inc., Mill Hall, PA). The retinoids were administered daily for 7 days/week by gastric gavage using a 20-gauge gavage needle in a volume of 0.1 ml containing sesame oil (vehicle), or 0.3 or 3 µg/kg TTNPB, or 10 or 100 mg/kg LGD1069. TTNPB high-dose (3 µg/kg) and low-dose (0.3 µg/kg) mice were treated from 8 weeks of age until sacrifice (up to 25 weeks). The TTNPB low dose (0.3 µg/kg) mice were treated inadvertently with 30 µg/kg for 1 week, but treatment was changed to 0.3 µg/kg for the remainder of the experiment (weeks 9–25). LGD1069 low-dose (10 mg/kg) mice were treated from 6 to 7 weeks until sacrifice. Because of their small size when young, the mice on high dose of LGD1069 (100 mg/kg) were initially treated with 50 mg/kg and then changed to a 100 mg/kg dose at 7 weeks of age. Tumor measurements were made with electronic calipers (Mitutoyo, Utsonomiya, Japan), and tumor volume was determined by multiplying the square of the width by the length and dividing by two. Individual tumor size and tumor location for each animal was recorded. Weights of all of the mice were recorded weekly.
At the time of sacrifice, each tumor was resected, and separate portions were: (a) processed for histological analysis; or (b) explanted into tissue culture to prepare in vitro tumor cell lines. These cells were grown in DMEM containing 10% FBS, 1% glutamine, 1% penicillin/streptomycin, and 1% Fungizone (Invitrogen, Carlsbad, CA).
Biomarkers and Histological Analysis.
Histology was performed as described previously (17)
. Briefly, samples were fixed in 10% neutral buffered formalin (10% formaldehyde, phosphate-buffered) overnight and then embedded in paraffin. Tissue sections were then mounted on slides and processed for H&E staining.
The immunohistochemical analysis of phospho-histone H3 (mitosis marker) was performed using a modified avidin-biotin complex technique as described in a previous study (20) . Briefly, tissue sections were deparaffinized in xylene and rehydrated in a series of ethanol solutions (100% to 50%). The sections were then microwaved for 15 min to retrieve antigens in 0.01 M citric acid solution. The endogenous peroxidase activity was blocked by incubation in a 1% methanolic hydrogen peroxide solution for 30 min. This was followed by preincubation with 20% normal goat serum to minimize nonspecific binding of the second antibody. The sections were then incubated at 23°C for 4 h with polyclonal mouse antiphospho-histone H3 antibody from Upstate Biotechnology (Lake Placid, NY) diluted at 1:50 in PBS. After being washed three times in PBS, the sections were incubated with biotinylated goat antirabbit IgG (H+L; Vector) for 30 min at 23°C and then incubated with the ABC kit (Vector Laboratories, Burlingame, CA) for 30 min in the dark. This was followed by incubation with 3-amino-9-ethylcarbazole (Sigma Chemical Co., St. Louis, MO) solution for 10 min to visualize the peroxidase complex. The sections were finally mounted with Aqua mount medium under coverslips. Control sections were incubated with normal goat IgG instead of primary antibodies or with the second antibody only.
The stained sections were reviewed and scored using an ocular grid. The percentage of positive cells was determined for five independent samples in each treatment group, and results were expressed as an average percentage.
Plasma Concentrations of Retinoids.
Concentration of retinoids was determined as described previously (17)
. Briefly, blood was collected in a heparinized tube, and plasma was separated by centrifugation. Plasma from 3 or 4 mice at each time point was isolated. Retinoid concentration was then analyzed by high-performance liquid chromatography as described previously (17)
.
Statistical Analysis of Results.
Two outcome measures were considered in this study: tumor-free survival and tumor multiplicity. Tumor-free survival was defined from time of birth to first appearance of a tumor (palpable masses 
100 mm3). Tumor-free survival curves were estimated by the Kaplan-Meier product limit method and compared using the generalized Wilcoxon test. Tumor multiplicity was determined by counting total number of tumors occurring in each animal up to the time of sacrifice. Multiplicity was summarized by means and standard errors, and compared by ANOVA.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
shows the structure of the retinoids used in this study. Previously the pan-9cRA (activates both RAR and RXR) was used (17)
. In this study, two synthetic receptor-selective retinoids were used: (a) TTNPB, which binds all RAR isotypes (21)
; and (b) LGD1069, which binds all RXR isotypes (22)
. TTNPB has been shown previously to be specific for the RAR receptor, whereas LGD1069 shows specificity for the RXR receptor (21
, 22)
.
|
, the pan-agonist 9cRA is able to activate both the RAR and RXR reporters at 20-fold and 5-fold, respectively. The RAR-selective retinoid, TTNPB, activated RAR-dependent transactivation, whereas it does not induce RXR reporter activity. LGD1069 slightly induced RARdependent transactivation but not as well as 9cRA or TTNPB. However, LGD1069 induced a 4-fold increase in the activity of the RXR reporter, similar to that seen with 9cRA. These results demonstrate that 9cRA is able to activate both RAR and RXR receptors, TTNPB activates RAR receptors, and LGD1069 activates predominately RXR receptors.
|
, the T47D cells were sensitive to all of these retinoids at different grades, with 9cRA causing the greatest growth inhibition. These results show that T47D breast cancer cells are sensitive to the pan-agonist 9cRA as well as the receptor-selective retinoids TTNPB and LGD1069.
|
Fig. 4A
shows a plot of the proportion of animals free of tumor versus age in days in animals treated with TTNPB. Whereas treatment with the highest dose of TTNPB prolonged time to tumor development, this difference did not reach the level of statistical significance (P = 0.08). Tumor development began at 90 days of age, and by 180 days (6 months) of age all of the vehicle-treated mice had developed tumors.
|
shows a Kaplan-Meier plot of proportion of animals free of tumors in mice treated with LGD1069. Treatment with the high dose of LGD1069 significantly prolonged time to tumor development (P = 0.05). Both the RAR-selective and RXR-selective retinoid delayed time to tumor development, although the RXR-selective retinoid caused a more significant delay.
As shown in Fig. 4
and in Table 1
, in mice treated with TTNPB, median time to tumor development was prolonged in the TTNPB-treated mice as compared with vehicle-treated mice (131 days for vehicle versus 142 days for 0.3 µg/kg TTNPB and 154 days for 3.0 µg/kg TTNPB; P 0.05). In mice treated with low dose of LGD1069 (10 mg/kg), both the control and LGD1069-treated mice showed a similar time to tumor development (130 days). However, mice treated with 100 mg/kg dose of LGD069 showed a significant delay in tumor development (156 days; P = 0.05 by the generalized Wilcoxon test).
|
. Specifically, the control mice developed an average of 2.9 tumors/mouse, whereas the LGD1069-treated mice developed 2.4 tumors in the 10 mg/kg LGD1069 group and 1.4 tumors in the 100 mg/kg LGD1069 group. This difference in tumor multiplicity between the control and high dose-treated animals was highly statistically significant (P 0.03 as assessed by ANOVA), and is similar to 9cRA, which showed a 50% reduction in tumor multiplicity (17)
. On the other hand, in the mice treated with TTNPB, there was no significant change on tumor multiplicity. The control mice as well as both treatment groups showed a similar number of tumors per mouse (approximately three tumors per mouse; P 0.91).
The toxicity of these retinoids is shown in Table 2
. All of the mice treated with the high dose of TTNPB showed skin erythema and hair loss, whereas no toxicities were seen in mice treated with LGD1069. The toxicities seen with TTNPB were similar to those seen with treatment with 9cRA. In addition, weight loss was observed in TTNPB-treated mice. In mice treated with LGD1069, no observable cutaneous toxicities or weight loss were observed. These results suggest that the RAR-selective retinoid, TTNPB, is highly toxic, whereas the RXR-selective retinoid, LGD1069, is nontoxic.
|
. Comparison of tumor samples showed no significant difference in morphology or nuclear grade. These results suggest that treatment with receptor-selective retinoids do not induce differentiation of the tumor cells that arise in treated animals. Staining for the mitosis marker phosphorylatedhistone H3 shows that LGD1069 inhibited phosphorylated-histone H3 expression, whereas TTNPB did not (Fig. 5
, 5.9% for vehicle versus 5.2% for TTNPB and 5.7% for vehicle versus 3.8% for LGD1069). This result is consistent with the inhibition of tumor formation and tumor multiplicity induced by LGD1069.
|
Plasma levels of TTNPB were undetectable by the methods used. Submicromolar concentrations of TTNPB were beyond the sensitivity of our high-performance liquid chromatography assay. However, concentrations were high enough to induce significant toxicities in the mice. Fig. 6A
shows the average plasma concentration over time after a single dose of LGD1069 (either 10 or 100 mg/kg). As shown in Table 3
, the Tmax was 30 minutes after a single dose of LGD1069 for both doses. Peak plasma concentrations achieved after a single dose were 2.61 and 58.07 µM for 10 mg/kg and 100 mg/kg, respectively.
|
|
shows the average plasma concentration over time after a dose of LGD 1069 in mice that were chronically treated with either 10 mg/kg (low dose) or 100 mg/kg (high dose) of LGD1609 for 28 days. As shown in Table 3
, the Tmax after chronic dosing was 30 min for the high dose and 60 min for the low dose. Plasma concentrations of LGD1069 after a single dose in chronically treated mice reached a lower maximal level (3.72 and 8.16 µM for 10 and 100 mg/kg, respectively) than compared with those in the single dose. Area under the curve values at 28 days were 43% and 87% lower than the area under the curve values after a single dose at the 10 and 100 mg/kg doses, respectively. These results suggest that chronic dosing of LGD1069 induces enzymes, which metabolize LGD1069. The results demonstrate that doses of 100 mg/kg used in these studies can achieve peak plasma levels up to 8 µM in chronically treated animals. These levels are consistent with levels that inhibit breast cell growth in vitro.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Studies of the C3(1)-SV40 transgenic mice suggest that tumors arising in these mice are less dependent on estrogen (19)
. The invasive carcinomas lose ER- expression early during tumor progression and appear to be hormone independent (19)
. Thus, these mice may serve as a model for ER-negative breast cancer. Our data with 9cRA (17)
and the data here with the receptor-selective retinoids demonstrate that retinoids can suppress the development of ER-negative tumors.
Suppression of tumor development by LGD1069 is relatively modest in comparison to the dramatic suppression reported by Gottardis et al. (23) in the NMU-induced rat mammary tumor model. In the NMU rat model, a 90% reduction in tumor burden and incidence was observed (23) . As discussed previously (17) , the differences in efficacy may be because of tumors that arise from different pathways in these two models i.e., the NMU carcinogen induces ras mutations, whereas the SV40 Tag inactivates the p53 and Rb tumor suppressor gene proteins. Just as we observed in the present study, Gottardis et al. (23) also observed no signs of toxicities in the rats treated with LGD1069.
The ability of RXR receptor-selective retinoids, particularly the RXR-selective retinoid LGD1069, to suppress tumor development without toxicity in this and other animal models demonstrates that RXR-selective retinoids are promising agents for the prevention of cancer. Retinoids may be most useful when combined with antiestrogens to prevent breast cancer development. Studies have already been conducted using retinoids in combination with antiestrogens such as tamoxifen and raloxifene and have shown when combined that these agents may have increased ability to prevent cancer (16 , 24, 25, 26, 27) . More recently, studies by Bischoff et al. (28) have shown that a combination of LGD1069 with the antiestrogen tamoxifen had an increased efficacy on NMU-induced mammary tumors.
On the basis of preclinical studies of LGD1069, this RXR-selective retinoid has already been tested in human clinical trials. In Phase I clinical trials for the treatment of cancer (29 , 30) LGD1069 was found to suppress the growth of cutaneous lymphoma and has now been approved for the treatment of cutaneous T-cell lymphoma (31) . The first cancer prevention trial using LGD1069 has just been activated at our institution. In this trial, LGD1069 is being used as a chemopreventive agent in women at high risk of breast cancer. Thus, the results from this and other studies suggests that LGD1069 will be useful for the prevention of breast cancer and may be particularly effective in combination with antiestrogens.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
1 Supported by NIH CA78480 (to P. H. B. and K. W.), NIH CA54174 (to J. G. K.), and P30CA54174 Cancer Center Support Grant to the San Antonio Cancer Institute 
2 To whom requests for reprints should be addressed, at Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, Houston, TX 77030. Phone: (713) 798-1600; Fax: (713) 798-1657; E-mail: pbrown{at}breastcenter.tmc.edu
3 The abbreviations used are: RAR, retinoic acid receptor; 9cRA, 9-cis retinoic acid; RXR, retinoid X receptor; Tag, T-antigen; ER, estrogen receptor; NMU, N-nitroso-N-methylurea; ß-gal, ß-galactosidase.
Received 9/28/01; revised 1/31/02; accepted 2/ 7/02.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
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]
|
|
| ||||||
