Abstract A54: Combining the rexinoid bexarotene with tamoxifen to prevent ER-negative mammary tumors in MMTV-erbB2 mice

Abstract

Abstract Background: Retinoids, vitamin A analogues that bind to retinoic acid receptor (RAR), play an important role in regulating cell proliferation and differentiation. Our previous studies demonstrated that related molecules, rexinoids (Bexarotene (LGD1069) and LGD100268), that bind the RXR receptor, suppress but do not totally prevent ER-negative mammary tumorigenesis. Using a transgenic mouse model of ER-negative breast cancer (MMTV-erbB2 mice), our laboratory demonstrated that bexarotene delays but does not totally prevent ER-negative mammary tumorigenesis with minimal toxicity. We hypothesized that bexarotene in combination with the anti-estrogen drug tamoxifen would more effectively prevent the development breast cancer. To test this hypothesis we treated MMTV-erbB2 mice with bexarotene, tamoxifen, or the combination from the age of 3 months to 9 months and monitored the mice for mammary tumors. Methods: Virgin MMTV-erbB2 mice at age of 3 months were used for these studies. A defined diet was used (AIN-76A). Mice were randomized into 4 groups (10 mice per group): 1) Tamoxifen control (Sham pellets) and bexarotene control (sesame oil), 2) Tamoxifen control (Sham pellets) and bexarotene (50mg/kg), 2) Tamoxifen pellets (2.5mg/pellet, 90-day-release) and bexarotene control (sesame oil), 4) Tamoxifen pellets (2.5mg/pellet, 90-day-release) and bexarotene (50mg/kg). Tamoxifen or sham pellets were replaced once after 90 days to deliver 180 days of tamoxifen (from age 3 months to 9 months). Bexarotene or sesame oil control was administered by gastric gavage daily (5 days per week) for 180 days (from age 3 months to 9 months). The mice were observed daily for tumor formation, weights were recorded weekly, and tumors were measured twice a week. Mice were sacrificed when tumor sizes exceeded 1500mm3. Analysis of time to tumor formation (defined as the time to develop a 100mm3 tumor) was the primary endpoint of these studies. Analysis of the expression of mammary tissue biomarkers is ongoing. Results: Bexarotene and tamoxifen as single agents slightly delayed the development of mammary tumors in these mice. However, the combination of bexarotene and tamoxifen was much more effective. By 350 days of age, 100% of the control animals developed mammary tumors, while only 10% of the animals treated with bexarotene and tamoxifen developed mammary tumors. This difference in time to tumor development is highly statistically significant (p <0.05; Generalized Wilcoxon test). These mice are still being followed, and updated results will be presented. We are now conducting biomarker studies to measure the effect of tamoxifen, bexarotene, and the combination on the expression of the erbB2 transgene, the estrogen receptor, and on markers of proliferation (Ki67 and cyclin D1) and apoptosis (cleaved caspase 3). Conclusions: The combination of bexarotene and tamoxifen is highly effective at preventing ER-negative mammary tumors in MMTV-erbB2 mice. These preclinical results suggest that combining a rexinoid with an anti-estrogen drug may be useful to prevent both ER-positive and ER-negative breast cancer in humans. These studies were supported by NIH R01 grants (CA101211) and by a Breast Cancer SPORE grant (P50 CA58183). Citation Information: Cancer Prev Res 2010;3(1 Suppl):A54.