Nicastrin regulates breast cancer stem cell properties and tumor growth in vitro and in vivo.

摘要: Nicastrin (NCT) is a crucial component of the γ-secretase (GS) enzyme, which prompted investigations into its biological role in cancer. We have previously shown that nicastrin overexpressed breast cancer (BC), conferring worse overall survival invasive, ERα negative patients. Here, we used 2D and 3D Matrigel, anchorage-independent growth conditions xenograft mouse model to assess impact on stem cell (BCSC) propagation invasion vitro tumor vivo. Stable knockdown HCC1806 cells reduced by 51.4 ± 1.7%, accompanied morphological change rounded phenotype down-regulation vimentin, Snail, Twist, MMP2, MMP9. observed reduction pool CD44(+)/CD24(-) ALDH1 high threefold twofold, respectively, 2.6-fold mammospheres formation. overexpression nontransformed MCF10A caused an induction epithelial mesenchymal regulators, as well fivefold increased activity, enrichment for cells, 3.2-fold enhanced mammosphere-forming capacity. Using γ-sescretase inhibiton, Notch1/4 siRNA, Akt inhibition, show regulates partly through Notch1 pathway. Exploiting serial dilution transplantation expressing stably depleted nicastrin, vivo, demonstrate inhibition may be relevant tumorigenicity cells. These data could serve benchmark development nicastrin-targeted therapies