Abstract 180: Inhibition of tumorigenesis by a novel Gemini vitamin D analog BXL0124 and a synthetic triterpenoid CDDO-Im in MMTV-HER2/neu transgenic mice.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC HER2 amplification is one of major genetic alterations in breast cancer, representing about 20% breast cancer cases. Gemini vitamin D analogs and synthetic triterpenoids have been shown to repress the growth of HER2-overexpressing breast cancer cells and inhibit mammary tumorigenesis of MMTV-HER2/neu transgenic mice. In previous leukemia studies, CDDO and its derivatives have been shown to synergize with vitamin D or vitamin D analogs to induce monocytic differentiation, demonstrating the potential combinatory effects for cancer prevention. In the present study, we investigated the anti-cancer activity of a novel Gemini vitamin D analog BXL0124, a potent synthetic triterpenoid CDDO-Im alone and in combination utilizing the MMTV-HER2/neu transgenic mouse model. BXL0124 (0.3 μg/kg body weight), CDDO-Im (3 μmole/kg body weight) or their combination was orally administered to MMTV-HER2/neu transgenic mice three times a week, beginning at 12 weeks of age. The body weight and tumor size of each mouse were measured weekly, and the mice were sacrificed when they were 56 weeks old. BXL0124, CDDO-Im and their combination delayed the development of MMTV-HER2/neu mammary tumors. The tumor multiplicity was decreased by BXL0124 (0.84), CDDO-Im (0.65, p<0.05) and their combination (0.53, p<0.05) compared to control (1.11). The averaged tumor weight was also reduced by BXL0124 (0.63 g), CDDO-Im (0.44g, p<0.05) and their combination (0.43 g, p<0.05) compared to control (0.89 g). In MMTV-HER2/neu mammary tumors, the activation of HER2 and EGFR as well as downstream signaling molecules, including JAK2, Src, Mek1/2 and Erk1/2, were markedly repressed by BXL0124, CDDO-Im and their combination. The protein levels of cyclin D1, c-Myc, PCNA and Bcl2 were decreased, whereas the protein level of p21 was increased by BXL0124, CDDO-Im and their combination. While HER2 was expressed in all tumor area, the activation of HER2 was found predominantly in the front invading edge area of MMTV-HER2/neu mammary tumors. All three treatments markedly decreased the activation of HER2 signaling at the front invading edge area. In conclusion, our study demonstrated that BXL0124, CDDO-Im and their combination may be promising chemopreventive agents targeting the HER2 signaling pathway in HER2-positive breast cancer. (This work was supported in part by the National Institutes of Health National Cancer Institute R01-CA-127645 and the National Institutes of Health National Institute of Environmental Health Science Grant ES005022.) Citation Format: Jae Young So, Amanda K. Smolarek, Hubert Maehr, Milan Uskokovic, Karen Liby, Michael B. Sporn, Nanjoo Suh. Inhibition of tumorigenesis by a novel Gemini vitamin D analog BXL0124 and a synthetic triterpenoid CDDO-Im in MMTV-HER2/neu transgenic mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 180. doi:10.1158/1538-7445.AM2013-180