Abstract 1248: The Gemini vitamin D analogue BXL0124 inhibits Notch signaling via HES1, resulting in the reduction of CD44+/CD24-/low subpopulation and proliferation of MCF10DCIS cells

Activation of Notch signaling is correlated with poor prognosis and decreased survival of breast cancer patients. Recent studies reported that Notch signaling plays an important role for the maintenance of tumor-initiating cells in breast cancer. Using MCF10DCIS.com human breast cancer cells (MCF10DCIS), which contain tumor-initiating subpopulation (CD44+/CD24-/low), we demonstrated that the Gemini vitamin D analog, BXL0124, reduced the tumor-initiating subpopulation in vitro and repressed the growth of MCF10DCIS xenograft tumors in vivo. In the present study, we investigated Notch signaling in CD44+/CD24-/low and CD44+/CD24+ subpopulations of MCF10DCIS cells and determined whether BXL0124 represses tumor-initiating subpopulation of breast cancer by targeting Notch signaling. CD44+/CD24-/low subpopulation showed higher Notch1 activation and cell proliferation than CD44+/CD24+ subpopulation in MCF10DCIS cells. To investigate the effects of BXL0124 on Notch signaling, the protein levels of Notch receptors and their ligands were determined. BXL0124 decreased activated Notch1 (c-Notch1) as well as its ligands, Jagged1, Jagged2 and DLL1. However, total Notch1 was not affected by BXL0124, suggesting that BXL0124 inhibits Notch signaling by decreasing Notch ligands. A downstream target of Notch signaling, cMyc, and cell proliferation were reduced by BXL0124. The inhibition of Notch1 activation by BXL0124 was blocked with knock-down of the vitamin D receptor (VDR), indicating that it...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Prevention Research Source Type: research