Abstract 945: Sca-1 deficiency enhances the chemopreventive activity of a peroxisome proliferator-activated receptorγ (PPARγ) agonist

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Stem cell antigen-1 (Sca-1, Ly6A) is a glycerophosphatidylinositol (GPI)-anchored membrane protein that was first identified as a murine marker of activated lymphocytes with stem cell-like properties. Although Sca-1 is widely used to enrich for stem cells in various tissues, little is known about its function and associated signaling pathways in development and tumorigenesis. Therefore, the role of Sca-1 in mammary gland development and tumorigenesis was undertaken using Sca-1 null mice. Sca-1-deficient animals exhibited slower ductal development in an age-dependent manner, and expressed increased p21Cip1 and reduced pRB, as well as a diminished response to progestin and estrogen stimulation. Mammary epithelium from Sca-1-null mice expressed increased PTEN, and reduced PDK1, AKT and c-Src activation. Significantly, the Sca-1 null mammary gland expressed increased PPARγ and reduced PPARδ, which resulted in a 10-fold increase in the ratio of PPARγ to PPARδ. In concordance with this phenotype, Sca-1 null mice exhibited a delay in progestin/DMBA-mediated mammary carcinogenesis, and were highly sensitive to the chemopreventive effects of PPARγ agonist GW7845, where tumorigenesis was inhibited by 90%. In contrast, tumor formation in Sca-1 null mice was unaffected by PPARδ agonist GW501516. Since GPI-anchored receptors are known to be associated with members of the c-Src tyrosine kinase family, we assessed if reduction of Sca-1 by RNAi affected c-Src activity, and if reduced c-Src activity may have contributed to increased GW7845 sensitivity. Lentivirus-mediated expression of Sca-1 shRNA in mammary tumor cells markedly reduced c-Src activation. In contrast, overexpression of c-Src, but not kinase-dead c-Src, inhibited PPARγ-dependent reporter gene activity and associated with PPARγ. These data suggest for the first time that loss of Sca-1 upregulates PTEN, attenuates c-Src and enhances PPARγ agonist sensitivity. Thus, targeting Sca-1 or its human homolog may be a useful approach to amplify the chemopreventive activity of PPARγ agonists. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 945.