Abstract 2884: Interferon Beta (IFN-B) re-activates canonical type I IFN signaling to differentiate breast cancer stem cells (CSCs) and suppress mesenchymal/CSC driven tumor recurrence

Abstract

Abstract Tumor recurrence remains a major therapeutic obstacle to curing breast cancer. Cytokines within the breast tumor microenvironment (TME) influence recurrence following chemotherapy by altering the balance between mesenchymal CSC (MES/CSC) and epithelial non-CSC (EP/non-CSC). Here, we find that transformed breast MES/CSC express elevated levels of Un-phosphorylated Interferon Stimulated Gene Factor 3 (U-ISGF3), which is composed of STAT1 and STAT2 lacking phosphorylation of their tyrosine residues, and IRF9. Elevated expression of the U-ISGF3 proteins in breast cancer has previously been linked with resistance to ionizing radiation, thus we hypothesized that the U-ISGF3 complex is important for maintaining MES/CSC properties. However, knockdown of IRF9, the critical DNA binding component of this complex, or STAT1 did not alter the MES/CSC phenotype. Moreover, ISGF3 transcriptional targets were actually repressed in MES/CSC relative to EP/non-CSC, suggesting that elevated U-ISGF3 may act as a repressor in MES/CSC. Interestingly, we found that an MES/CSC program independent of IFN-B, was responsible for mediating U-ISGF3 expression. We therefore hypothesized that stimulating MES/CSC with IFN-B would phosphorylate the ISGF3 proteins and engage canonical IFN-B mediated inhibition of MES/CSC properties. Acute exposure to IFN-B led to the phosphorylation of ISGF3 in MES/CSC and induced the transcription of IFN-B responsive genes. Continuous exposure to IFN-B maintained Phosphorylated ISGF3 (P-ISGF3) which partially reverted the MES/CSC phenotype, resulting in the repression of mesenchymal markers (Vimentin and Slug), re-expression of Ep/non-CSC markers (CD24) and functionally inhibited colony formation in soft agar and migratory capability. In line with these observations, data from triple-negative breast cancer (TNBC) patients confirmed that increased expression of IFN-B responsive genes correlates with decreased expression of a CSC gene signature, and correlates with improved recurrence-free survival. Taken together, our findings demonstrate that IFN-B mediated signaling promotes the differentiation of MES/CSC by phosphorylating U-ISGF3, resulting in the suppression of MES/CSC-driven tumor recurrence. Future studies will examine the mechanism by which IFN-B mediated P-ISGF3 suppresses MES/CSC properties and whether elevation of U-ISGF3 can predict which patients would be candidates for an IFN-B therapy to phosphorylate STAT1 and STAT2, thus suppressing MES/CSC tumor recurrence. Citation Format: Mary R. Doherty, Damian J. Junk, HyeonJoo Cheon, George R. Stark, Mark W. Jackson. Interferon Beta (IFN-B) re-activates canonical type I IFN signaling to differentiate breast cancer stem cells (CSCs) and suppress mesenchymal/CSC driven tumor recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2884. doi:10.1158/1538-7445.AM2017-2884