Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069.
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 microg/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 approximately 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 < or = 0.03). TTNPB-treated mice showed a delayed median time to tumor development (131 days for vehicle versus 154 days for 3.0 microg/kg TTNPB; P < or = 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.
Wu
Kendall
K
Breast Center, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Kim
Hee-Tae
HT
Rodriquez
Jenny L
JL
Hilsenbeck
Susan G
SG
Mohsin
Syed K
SK
Xu
Xiao-Chun
XC
Lamph
William W
WW
Kuhn
John G
JG
Green
Jeff E
JE
Brown
Powel H
PH
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood; D001565:Benzoates / Q000008:administration & dosage / Q000097:blood; D000077610:Bexarotene; D014408:Biomarkers, Tumor / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000517:prevention & control; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage* / Q000097:blood; D006657:Histones / Q000097:blood / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D018168:Receptors, Retinoic Acid / Q000008:administration & dosage* / Q000502:physiology; D047488:Retinoid X Receptors; D012176:Retinoids / Q000008:administration & dosage / Q000097:blood; D012680:Sensitivity and Specificity; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000097:blood; D013997:Time Factors; D014157:Transcription Factors / Q000008:administration & dosage* / Q000502:physiology; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D001565:Benzoates; D014408:Biomarkers, Tumor; D006131:Growth Inhibitors; D006657:Histones; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D000077610:Bexarotene