Abstract 4886: Targeting WNT1-inducible signaling pathway protein 2 (WISP2) alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression

Abstract

Abstract The molecular basis for the resistance of tumor cells to cell-mediated cytotoxicity remains poorly understood and thus poses a major challenge for cancer immunotherapy. The present study was designed to determine whether the WNT1-inducible signaling pathway protein-2 (WISP2, also referred to as CCN5), a key regulator of tumor cell plasticity, interferes with tumor susceptibility to Cytotoxic T Lymphocytes (CTL)-mediated lysis. We found that targeting WISP2 signaling in human breast adenocarcinoma MCF7 cells impairs CTL-mediated cell killing by a mechanism involving Kruppel-like factor-4 (KLF-4) induction and microRNA-7 (miR-7)downregulation. Inhibition of TGF-β signaling using the A83-01 inhibitor in MCF7-shWISP2 cells resulted in a significant reversal of the Epithelial-to-Mesenchymal Transition (EMT) phenotype, the expression of stem cell marker KLF-4 and a partial recovery of target susceptibility to CTLs. More importantly, we showed that silencing of KLF-4 was accompanied by a reduction in MCF7-shWISP2 resistance to CTLs. Using human breast cancer tissues, we demonstrated the coexpression of KLF-4 with EMT markers and TGF-β pathway. More importantly, we found that KLF-4 expression was accompanied by miR-7 inhibition, which is partly responsible forimpairing CTL-mediated lysis. Thus, our data indicate that WISP2 plays a role in regulating tumor cell susceptibility through EMT by inducing the TGF-β signaling pathway, KLF-4 expression and miR-7 inhibition. These studies indicate for the first time that WISP2 acts as an activator of CTL-induced killing and suggests that the loss of its function promotes evasion of immunosurveillance and the ensuing progression of the tumor. Citation Format: Intissar Akalay, salem chouaib, jean-paul thiery. Targeting WNT1-inducible signaling pathway protein 2 (WISP2) alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. [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 4886. doi:10.1158/1538-7445.AM2014-4886