C/EBPδ demonstrates a dichotomous role in tumor initiation and promotion of epithelial carcinoma

Abstract

High Grade Serous Ovarian Cancer (HGSC) originates primarily from the fallopian tube epithelia. It is postulated that pre-malignant cells can migrate and implant onto the surface of the ovary. We previously reported that genes differentially expressed in the ovulatory phase can predispose the fallopian tube epithelia to transformation. Since ovulation is frequent, we hypothesize that C/EBPδ, a gene expressed in the luteal phase, can modulate the transformation of p53-mutated fallopian tube epithelial cells. Here, we show significantly decreased expression of C/EBPδ in HGSC compared to normal fallopian tube epithelia. We demonstrate that C/EBPδ, lost early during disease progression, is associated with a mesenchymal phenotype in normal fallopian tube epithelia. However, in a subset of HGSC, C/EBPδ expression is maintained. This pre-malignant subset of cells, that express C/EBPδ, promotes a mesenchymal to epithelial transition and promotes migration in the context of p53 mutation. While C/EBPδ over-expression induces cellular characteristics conducive to an EMT-MET switch, it also behaves as a tumor-suppressor, inhibiting cell cycle progression, indicative of its complex role in the pathogenesis of the disease.