s-SHIP Promoter Expression Identifies Mouse Mammary Cancer Stem Cells

Abstract

Summary: During normal mammary gland development, s-SHIP promoter expression marks a distinct type of mammary stem cells, at two different stages, puberty and early mid-pregnancy. To determine whether s-SHIP is a marker of mammary cancer stem cells (CSCs), we generated bitransgenic mice by crossing the C3(1)-SV40 T-antigen transgenic mouse model of breast cancer, and a transgenic mouse (11.5kb-GFP) expressing green fluorescent protein from the s-SHIP promoter. Here we show that in mammary tumors originating in these bitransgenic mice, s-SHIP promoter expression enriches a rare cell population with CSC activity as demonstrated by sphere-forming assays in vitro and limiting dilution transplantation in vivo. These s-SHIP-positive CSCs are characterized by lower expression of Delta-like non-canonical Notch ligand 1 (DLK1), a negative regulator of the Notch pathway. Inactivation of Dlk1 in s-SHIP-negative tumor cells increases their tumorigenic potential, suggesting a role for DLK1 in mammary cancer stemness. : Bourette and colleagues assess renewal and differentiation potential of s-SHIP-expressing cells in mouse mammary tumors, by in vitro sphere-forming assay and in vivo transplantation. Their data indicate that s-SHIP expression marks a distinct population of mammary cancer stem cells and unveils a potential role of Dlk1, a negative regulator of the Notch pathway, in the regulation of mammary tumor cell stemness. Keywords: breast cancer, CSC, s-SHIP, transgenic mouse, mammary tumor, DLK1, notch, SHIP1