Abstract 184: A gemini vVitamin D analog, BXL0124, inhibits mammary tumorigenesis by delaying the transition of ductal carcinoma in situ to iInvasive breast carcinoma.
Authors: Wahler Joseph , So Jae Young , Smolarek Amanda , Maehr Hubert , Uskokovic Milan , Suh Nanjoo 
Published: August 2014

The transition of ductal carcinoma in situ (DCIS) to invasive carcinoma is a crucial event in the progression of breast tumors. DCIS is a noninvasive breast cancer that harbors various grades of lesions ranging from non life threatening to invasive type lesions. The disappearance and breakdown of the myoepithelial cell layer and basement membrane in DCIS has been identified as a major event in the progression from DCIS to invasive carcinoma. We have previously reported that a novel Gemini vitamin D analog, 1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124), inhibits the growth of MCF10DCIS.com xenografted tumors in immunodeficient mice without hypercalcemic toxicity. Based on this knowledge, we have investigated whether BXL0124 blocks or delays the progression of DCIS. In the present study, MCF10DCIS.com cells (1x106 cells/mouse) were injected into the mammary fat pad of nu/nu mice. The mice were then treated with BXL0124 (0.1μg/kg) over weeks 1, 2, and 3. Mammary glands and tumors were analyzed over the course of three weeks to determine the effects of BXL0124. The myoepithelial marker, smooth muscle actin (SMA), and the luminal marker, cytokeratin 18 (CK18), were used to analyze tumor histology. The inhibitory effect of BXL0124 treatment on cell proliferation was determined by the cell proliferation marker, proliferating cell nuclear antigen (PCNA). BXL0124 showed a 53% and 60% reduction in the tumor volume by week 2 and 3, respectively. The myoepithelial structure of DCIS was maintained in the treatment group, whereas loss of the myoepithelial layer was evident in the control group. The treatment with BXL0124 also decreased cell proliferation of DCIS luminal cells compared to the control group, suggesting that growth potential of luminal cells was reduced by BXL0124. In conclusion, the Gemini vitamin D analog BXL0124 inhibits the progression of MCF10DCIS.com xenografted mammary tumors in part by maintaining the vital myoepithelial layer within the tumors and by reducing proliferation rate of the luminal cells. Our results suggest a novel mechanism in the cancer preventive action of BXL0124 during the progression of DCIS like lesions to invasive carcinoma. (This work was supported in part by the National Institutes of Health National Cancer Institute R01-CA127645 and the National Institute of Environmental Health Sciences Grant ES005022).

Citation Format: Joseph Wahler, Jae Young So, Amanda Smolarek, Hubert Maehr, Milan Uskokovic, Nanjoo Suh. A gemini vVitamin D analog, BXL0124, inhibits mammary tumorigenesis by delaying the transition of ductal carcinoma in situ to iInvasive breast carcinoma. [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 184. doi:10.1158/1538-7445.AM2013-184