9-cis-Retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus40 T antigen-transgenic mice

Retinoids have been investigated as potential agents for the prevention and treatment of human cancers, These compounds play an important role in regu lating cell growth, differentiation, and apoptosis, 9-cis-Retinoic acid (9c RA) is a naturally occurring ligand with a high affinity for both the retin oic acid receptors and the retinoid X receptors, We hypothesized that treat ment with 9cRA would prevent mammary tumorigenesis in transgenic mice that spontaneously develop mammary tumors. To test this hypothesis, C3(1)-SV40 T antigen (Tag) mice, which develop mammary tumors by the age of 6 months, w ere treated daily p.o. with vehicle or two different dose Levels of 9cRA (1 0 or 50 mg/kg) from 5 weeks to 6 months of age, Tumor size and number were measured twice each week, and histological samples of normal and malignant tissue were obtained from each mouse at time of sacrifice. Our results demo nstrate that 9cRA suppresses mammary tumorigenesis in C3(1)-SV40 Tag-transg enic mice, Time to tumor development was significantly delayed in treated m ice; median time to tumor formation for vehicle-treated mice was 140 days v ersus 167 days for mice treated with 50 mg/kg 9cRA (P = 0.05), In addition, the number of tumors per mouse was reduced by >50% in mice treated with 9c RA (3.43 for vehicle, 2.33 For 10 mg/kg 9cRA, and 1.13 for 50 mg/kg 9cRA, P less than or equal to 0.002), Histological analysis of the mammary glands from vehicle and treated mice demonstrated that 9cRA treatment also did not affect normal mammary gland development, Immunohistochemical staining of n ormal and malignant breast tissue and Western blot analysis demonstrated th at SV40 Tag expression was not affected by treatment with retinoids, Single doses of 10 and 50 mg/kg resulted in peak plasma concentrations of 3.4 and 6.71 mu M, respectively. Daily doses of 9cRA for 28 days resulted in plasm a concentrations of 0.86 and 1.68 mu M, respectively, concentrations consis tent with that seen in humans treated with 9cRA in clinical trials. These r esults demonstrate that 9cRA suppresses mammary carcinogenesis in transgeni c mice without any major toxicity and suggest that retinoids are promising agents for the prevention of human breast cancer.