Abstract 3955: The tumor suppressor C/EBPdelta promotes hypoxia-induced EMT and expression of stem cell markers through inhibition of FBXW7: Implications for mammary tumor metastasis.

Abstract

Abstract The transcription factor CCAAT/enhancer binding protein delta (C/EBPδ) exhibits tumor-suppressor like-qualities such as downregulation of cyclin D1, and promotion of growth arrest and apoptosis. However, using a mouse model of mammary tumorigenesis (MMTV-Neu), we had found that C/EBPδ has dual functions. C/EBPδ suppresses primary tumor incidence while also augmenting metastatic progression. The pro-metastatic function of C/EBPδ can be correlated with a role in hypoxia adaptation and expression of pro-inflammatory genes and macrophage activation. C/EBPδ exerts both of these functions through inhibition of FBXW7, a component of SCF E3 ubiquitin ligase complex, which targets substrates such as c-myc and Notch for degradation (Balamurugan et al, 2010; Balamurugan et al., under revision). Hypoxia is believed to promote tumor progression in part by inducing epithelial-mesenchymal transition (EMT), which contributes to the generation of stem-like cancer cells (CSCs). In the present study, we found that hypoxia-induced EMT and expression of CSCs markers were compromised in Cebpd null primary tumor cells and in human breast tumor cells when C/EBPδ expression was silenced. On the other hand, silencing of the C/EBPδ-repressed gene FBXW7 was sufficient to induce a mesenchymal-like phenotype. Loss of FBXW7 has been shown to promote acquisition of stemness. In line with this notion, we found that overexpression of FBXW7 in the breast tumor cell line MDA-MB-468 reduced expression of aldehyde dehydrogenase 1 (Aldh1), C/EBPδ and the active form of NOTCH (NICD). Together, these data suggest that C/EBPδ augments - whereas its target FBXW7 prevents - EMT and breast cancer stem cell development, which may be an additional mechanism by which C/EBPδ promotes metastatic progression. Our current investigations are aimed at understanding how the different functions of C/EBPδ are integrated depending on cellular environment and context that results in its tumor promoting function despite its tumor suppressor role. Citation Format: Balamurugan Kuppusamy, Esta Sterneck. The tumor suppressor C/EBPdelta promotes hypoxia-induced EMT and expression of stem cell markers through inhibition of FBXW7: Implications for mammary tumor metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3955. doi:10.1158/1538-7445.AM2013-3955