Abstract B56: Rexinoid LG100268 and tamoxifen prevents mammary tumors in p53-null mammary gland mice

Abstract

Abstract Background: Breast cancer prevention is now possible using anti-estrogen drugs such as tamoxifen and raloxifene. However, the anti-estrogen drugs do not prevent all types of breast cancer. These drugs are useful for the prevention of estrogen receptor (ER)-positive breast cancers, but are unable to prevent the development of ER-negative breast cancer. ER-negative breast cancers are highly aggressive and are particularly difficult to treat. Thus, there is an urgent need to develop ways to prevent these life-threatening cancers. Using a transgenic mouse model of ER-negative breast cancer, our laboratory has previously demonstrated that LGD100268, a ligand to the RXR nuclear hormone receptor, prevents up to 90% of the ER-negative breast cancers in these mice. However, because this drug does not prevent all breast cancers in these mice, we have attempted to achieve more effective cancer prevention by combining two cancer preventive drugs. We hypothesized that the combination of the rexinoid LG100268 in combination with tamoxifen will more effectively prevent the development of ER-negative breast cancer. To test this hypothesis, we used the p53-null mouse model that develops both ER-positive and ER-negative mammary tumors to determine whether the combination of a rexinoid and an anti-estrogen is more effective than either treatment alone in preventing ER-positive and ERnegative mammary tumors. Methods: Using our standard transplant protocol, p53-null Balb/C donor mice was transplanted into both cleared inguinal mammary fat pads of Balb/C p53 wild-type mice. Mice were separated into 5 treatment groups (15 mice each). 1) Sham Control: 2) Vehicle Control: 3) Tamoxifen + Vehicle: 4) Sham pellet (5mg) + Rexinoid: (at 50mg/kg), 5) Tamoxifen + Rexinoid: Mice were treated for 60 days with each drug sequentially. Mice were observed daily for tumor formation and the percentage of tumor free mice were recorded. Tumor incidence and time to tumor formation was analyzed. The expression of mammary tissue biomarkers was done using immunohistochemistry and real time QRT-PCR. Results: 38% of sham and 41% vehicle control animals developed tumors. Sequential treatment with tamoxifen and LGD100268 prevented more (8% incidence) than tamoxifen (24% incidence) or LGD100268 (20% incidence) alone. Proliferation markers Ki67 and cyclin D1 were markedly reduced in the mammary tissue from the mice treated with the combination therapy. We have also observed induction of rexinoid target genes ABCA1 and ABCG1, in the retinoid group and in the combination group. Conclusions: The combination treatment of rexinoid LG100268 and tamoxifen is more effective at preventing mammary tumors than either agent alone. Based on these studies, clinical trials using the combination of tamoxifen and rexinoids should be considered for the prevention of breast cancer in high-risk patients. Supported by NIH grants P50 CA58183 (PB, DM) and R01 CA101211 (PB, DM). Citation Information: Cancer Prev Res 2010;3(12 Suppl):B56.