Reduction Of Microrna-21 By Vitamin D Compounds During Ductal Carcinoma In Situ Transition To Invasive Ductal Carcinoma

MicroRNAs (miRNAs) are small RNA molecules of approximately 22 nucleotides in lengths that can negatively control target gene expression post-transcriptionally. There are currently more than one hundred known human miRNAs. miRNAs have been shown to play an important role in the development and progression of various types of cancer. In breast cancer, ductal carcinoma in situ (DCIS) is an early non-invasive precursor, which is known to progress to invasive ductal carcinoma (IDC) if left untreated. The involvement of miRNAs in the breast cancer progression from DCIS to IDC is still not well understood, and potential regulation of miRNAs by vitamin D compounds during the progression has not been tested. 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 progression of DCIS to IDC in vivo. To identify miRNAs that could potentially be involved in DCIS progression to IDC, we utilized the MCF10DCIS.com xenograft tumors. MCF10DCIS.com cells (10^6 cells/mouse) were injected subcutaneously into the rear flanks of nu/nu mice. The mice were then treated with BXL0124 (0.1 μg/kg) for 5 weeks. The critical DCIS to IDC transition occurred between weeks 3 and 4 in the in vivo lesions, and several microRNAs were assessed with respect to the DCIS to IDC transition at weeks 3 and 4. Among many miRNAs analyzed, miR-21, miR-24, and miR-140 were up-regulated in IDC lesions compared to DCIS lesions, whereas no marked changes were observed with respect to miR-200c, miR-let-7a, miR-26a, miR-34a, and miR-182. One of the miRNAs identified miR-21, is a well-known oncomir and overexpressed in breast carcinoma, mediating cell survival, proliferation, and metastasis. The increased expression of miR-21 was significant when DCIS lesions progressed to IDC, and this effect was diminished by the treatment with Gemini vitamin D, BXL0124, at week 4. In conclusion, vitamin D compounds reduce the levels of miR-21 during DCIS transition to IDC, potentially contributing to its preventive effects in breast cancer progression. Further investigation of the mechanisms of action by which vitamin D compounds regulate miR-21 should be considered. (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, Larry C. Cheng, Hubert Maehr, Milan Uskokovic, Nanjoo Suh. Reduction of microRNA-21 by vitamin D compounds during ductal carcinoma in situ transition to invasive ductal carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1912. doi:10.1158/1538-7445.AM2015-1912