Abstract 3326: Parallel EMT pathways mediated by epidermal growth factor, EpCAM and mesenchymal cadherins in benign endometriotic lesions and endometrial cancer
Authors: Ya-Ting Hsu, Joseph Liu, Peter A. Binkley, Robert S. Schenken, Rajshwar R. Tekmal, Tim H.-M. Huang, Nameer B. Kirma
Journal: Cancer Research (2014)

Abstract The endometrium is the major target of oncogenesis in the uterus. Endometrial tissue undergoes several cycles of disintegration and repair during women's reproductive years. The involvement of repair mechanisms that include transforming growth factor beta (TGF-beta) pathway may entail epithelial msenchymal transition (EMT) known to be involved in tissue repair. This suggests that the EMT program is inherent in endometrial epithelial cells and may be subverted during the development of invasive disease, whether benign such as endometriosis or malignant such as endometroid endometrial carcinoma. We therefore examined candidate mechanistic modulators of EMT in normal and malignant endometrial epithelial cells as well as endometrial carcinoma samples using cell signaling, gene expression and epigenetic regulation methodologies. Our evidence strikingly show that although both TGF-beta and epidermal growth factor (EGF) stimulated primary normal endometrial epithelial cell invasiveness, EGF was the main inducer of EMT in these cells. EGF also strongly induced EMT in endometrial cancer cells. In normal and malignant cells, Raf-1/MAPK mediated EGF actions. Interestingly, EGF stimulated epithelial adhesion molecule (EpCAM) cleavage and internalization of its intracellular domain EpICD into the nucleus to activate EMT-related genes such as mesenchymal cadherins. This was associated with loss of the epithelial marker E-cadherin and upregulation of its negative regulator Snail1. The involvement of EMT in aggressive endometrial malignancy was further confirmed in a permissive transcriptional epigenetic profile of mesenchymal cadherins in endometrial cancers with poor survival compared to a silenced epigenetic signature in less aggressive tumors. This epigenetic regulation including DNA methylation and histone modification was mediated by EpCAM, as shown in EpCAM-knockdown endometrial cancer cells, suggesting that EpCAM binding to target promoters maintains an open transcriptional conformation. Combined, our data suggest that while plasticity is required for endometrial regeneration during the menstrual cycles, committed epigenetic signatures may alter the path of normal tissue repair to aberrant growth associated with benign tumors or malignant growth. In concert, activation by cell signaling such as EGF/EpCAM may determine the extent of invasiveness and disease progression. Citation Format: Ya-Ting Hsu, Joseph Liu, Peter A. Binkley, Robert S. Schenken, Rajshwar R. Tekmal, Tim H.-M. Huang, Nameer B. Kirma. Parallel EMT pathways mediated by epidermal growth factor, EpCAM and mesenchymal cadherins in benign endometriotic lesions and endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3326. doi:10.1158/1538-7445.AM2014-3326