The Combination of Tamoxifen and the Rexinoid LG100268 Prevents ER-Positive and ER-Negative Mammary Tumors in P53-Null Mammary Gland Mice
Menée sur un modèle murin, cette étude montre qu'un traitement combinant le tamoxifène et le rexinoïde LG100268 peut réduire le risque de cancer du sein
In pursuit of effective therapeutic agents for the ER-negative breast cancer, we previously demonstrated that bexarotene reduced mammary tumor development by 75% in ErbB2 mice. To further improve the effectiveness of breast cancer prevention, we have now investigated the effects of a combinatorial therapy consisting of two cancer preventive drugs. Based on the hypothesis, rexinoid LG100268 plus tamoxifen would more effectively prevent the development of both ER-positive and ER-negative breast cancer. We treated p53-null mammary gland mice with tamoxifen and LG100268 individually and in combination. By 60 weeks, vehicle treated mice developed tumors in 52% of transplanted mammary glands while mice treated with tamoxifen and LG100268 developed tumors in only 13% of transplanted mammary glands. To further define the mechanistic effects of this combinatorial treatment, we investigated the effects of tamoxifen and LG100268 on mammary tissue biomarkers. In mammary tissue harvested before tumor development, the proliferation markers Ki67 and cyclin D1 were significantly reduced in mice treated with the combination therapy. In addition, rexinoid target genes ABCA1 and ABCG1 were induced in both the rexinoid and combination treatment groups, while expression remained constant in tamoxifen group. These results show that tamoxifen-LG100268 combinatorial treatment is more effective at preventing mammary tumors than either agent alone. In addition these studies have identified relevant tissue biomarkers that can be used to demonstrate the effect of these agents on mammary tissue. These results support the development of clinical trials of anti-estrogen and rexinoid combinatorial therapy for the prevention of high risk breast cancer patients.