Abstract C20: Reversal of mesenchymal phenotype of triple-negative breast cancer and glioblastoma cells and its therapeutic implication

Abstract

Abstract Mesenchymal transition is common to many aggressive cancers including breast, glioblastoma (GBM), lung and pancreatic cancers characterized by chemo/radiotherapy-resistance and cancer stem cell-like property. Claudin-low msenchymal subtype in triple-negative breast cancer (TNBC) is a major problem due to the lack of molecularly-targeting drugs. So far, we have identified an shRNA (shP1) which can induce mesenchymal to epithelial transition (MET) in shRNA library screening using positive selection reporter system in MDA-MB-231 mesenchymal TNBC cell line. Here, we have analyzed the effect of shP1 on morphology, transcription and cell proliferation in various mesenchymal cancer cell lines derived from breast, glioblastoma (GBM), lung and pancreatic cancers. The shP1 increased E-cadherin promoter-driven GFP in a wide range of mesenchymal cancers including brain, breast, pancreatic, lung origin. Drastic morphology change introduced by shP1 was observed both in 2D and 3D cultures (matrigel, collagen), reducing their invasive and branching morphogenesis, especially in U251 GBM and MDA-MB-231 TNBC cell lines. The shP1-introduced cells are more sensitive to EGFR-inhibition and paclitaxel in TNBC cell line, reminiscent of reversal of therapy-resistant phenotype. Gene expression analysis reveals alteration of pathways related to cell adhesion, ERRB signal pathway, apoptosis and cytokines signaling. Of note, shP1-introduced U251 cells increased gene expression characteristic of proneural subtype, indicating shP1 reverted the subtype from mesenchymal to proneural. These results suggest that although U251 and MDA-MB-231 cell lines are of different tissue origins, their mesenchymal property can be reverted by the same program targeted by single shRNA. These results provide a rationale of MET as therapeutic for a wide range of cancers with mesenchymal property. Citation Format: Kiyotsugu Yoshikawa, Hiroaki Sakai, Masahiro Shimazaki, Nobuhiro Okada, Yoshiaki Matsumoto, Ellis Reinherz, Masakazu Toi. Reversal of mesenchymal phenotype of triple-negative breast cancer and glioblastoma cells and its therapeutic implication. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C20.