9-cis-retinoic acid suppresses mammary tumorigenesis in MMTV-ErbB2/Neu-transgenic mice

Retinoids have been investigated as potential agents for the prevention and treatment of breast cancer. 9-cis-retinoic acid (9cRA), a naturally-occurring retinoid, has previously been shown to suppress mammary carcinogenesis in carcinogen-treated rats and in C3(1)-SV40 large T-antigen (TAG) transgenic mice. However, these models may not accurately model human breast cancer. Therefore, we have tested the ability of 9cRA to prevent mammary tumor formation in the MMTV-ErbB2/Neu transgenic mouse model. Tumors in these mice resemble human breast cancer and serve as a model of ErbB2-overexpressing breast cancers. We hypothesized that treatment with 9cRA would prevent mammary tumorgenesis in this model. Mice were treated six days per week with vehicle or 9cRA (either 10 mg/kg or 50 mg/kg) from three months to ten months of age. Tumor and weight measurements were taken weekly, and histological samples of normal and malignant tissue were obtained from each mouse at time of sacrifice. Our results demonstrate that 9cRA suppress mammary tumorgenesis in MMTV-ErbB2/Neu-tansgenic mice. Median time to tumor formation was significantly delayed in treated mice (275 days for vehicle as compared to > 400 days in mice treated with 50 mg/kg 9cRA, p=0.05). In addition, the number of tumors per mouse in 9cRA-treated mice was reduced compared to the number of tumors in vehicle-treated mice (1.38 for 50 mg/kg versus 1.50 for vehicle). The mice treated with 50 mg/kg 9cRA tolerated this dose for ten months. After that time, they developed typical retinoid toxicities including hair loss, skin erythema, and generalized weight loss. Because of these toxicities, treatment was stopped in the high dose group at 309 days. The mice treated with 10 mg/kg of 9cRA showed no observable toxicities and treatment was continued for a total of 516 days. Based on histological analysis, 9cRA treatment did not affect the normal mammary gland development. Immunohistochemical staining and Western blot analysis showed that ErbB2/Neu expression was not affected by the treatment with 9cRA. These data compared to that seen previously in SV40 Tag mice show that 9cRA is even more effective in MMTV-ErbB2/Neu mice. The finding that 9cRA suppresses mammary tumor formation in several different animal models confirms that retinoids are promising agents for the prevention of human breast cancers.