Abstract 1922: S-SHIP promoter expression identifies a putative cancer stem cell population in C3(1)/Tag murine mammary tumors

Abstract

Abstract Breast cancer is the most common cancer in women worldwide. The isolation and characterization of breast cancer stem cells (CSC) are crucial for understanding cancer biology and revealing potential therapeutic targets. One of the major issues in the study of CSC is the lack of reliable markers. A transgenic mouse model (Tg 11.5kb–GFP) was generated using the 11.5kb s-SHIP (stem-SH2-containing 5’-Inositol Phosphatase) promoter that specifically expressed enhanced green fluorescent protein (GFP) in embryonic and various tissue stem cells. In the mammary gland, previous experiments showed that GFP labels puberty cap cells and pregnancy basal alveolar bud cells, and it has been demonstrated that these mammary GFP+ cells are activated tissue stem cells. In order to determine if s-SHIP promoter expression could also mark mammary cancer stem cells, we generated a bi-transgenic mouse model by crossing Tg 11.5kb-GFP mice with Tg C3(1)/Tag mice. Tg C3(1)/Tag mice express SV40 T antigen under the regulatory control of the rat prostatic steroid binding protein C3(1) gene. In female mice, the transgene is expressed primarily in the mammary gland. Mice develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age. Here we show the presence of a rare population of GFP+ cells in mammary tumors of female bi-transgenic mice by using immunohistochemical and flow cytometry analysis. The GFP+ mammary cancer cells are also CD24+/CD49f+/CD29+. As compared to GFP- cells, GFP+ cells exhibit both a higher tumor sphere-forming potential, and a higher tumorigenicity when transplanted into SCID and FVB recipient mice. Moreover, upon subsequent transplantation, the GFP+ cells generated heterogeneous tumors that displayed properties similar to the primary tumor. Currently, we are conducting transcriptomic analysis of these GFP+ and GFP- cells in order to reveal differentially expressed genes. Altogether, these results suggest that s-SHIP promoter expression may be a new marker of mammary CSC that enables their identification and isolation via a single consistent parameter. Furthermore, our bi-transgenic C3(1)/Tag x 11.5kb-GFP mice provide a novel model for study of mammary cancer stem cells and investigation of potential therapeutic targets for breast cancer. Citation Format: Lu Tian, Chann Lagadec, Eric Adriaenssens, Emmanuel Bouchaert, Hélène Bauderlique-Le Roy, Xuefen LeBourhis, Roland P. Bourette. S-SHIP promoter expression identifies a putative cancer stem cell population in C3(1)/Tag murine mammary tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1922. doi:10.1158/1538-7445.AM2017-1922