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Interferon-Beta Represses Cancer Stem Cell Properties in Triple-Negative Breast Cancer

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Interferon-Beta Represses Cancer Stem Cell Properties in Triple-Negative Breast Cancer Interferon-beta represses cancer stem cell properties in triple-negative breast cancer Mary R. Dohertya,1, HyeonJoo Cheonb, Damian J. Junka,c, Shaveta Vinayakc,d,e, Vinay Varadanc,f, Melinda L. Tellig, James M. Fordg, George R. Starkb,c,1, and Mark W. Jacksona,c,1 aDepartment of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106; bDepartment of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195; cCase Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, OH 44106; dDepartment of Hematology/Oncology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106; eUniversity Hospitals Cleveland Medical Center, Cleveland, OH 44106; fDepartment of General Medical Sciences/Oncology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106; and gDepartment of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA 94305 Contributed by George R. Stark, November 10, 2017 (sent for review August 15, 2017; reviewed by Sendurai A. Mani and Ralph R. Weichselbaum) Triple-negative breast cancer (TNBC), the deadliest form of this of a heterogeneous mixture of tumor, immune, endothelial, and disease, lacks a targeted therapy. TNBC tumors that fail to respond stromal cells (7–11). Recent metaanalyses have identified a to chemotherapy are characterized by a repressed IFN/signal trans- number of TNBC subtypes, including two distinguishable by the ducer and activator of transcription (IFN/STAT) gene signature and presence or absence of tumor-infiltrating lymphocytes (TILs) and are often enriched for cancer stem cells (CSCs). We have found that IFN/signal transducer and activator of transcription (IFN/STAT) human mammary epithelial cells that undergo an epithelial-to- signaling (3, 4, 12). Immune-responsive TNBCs are defined by the mesenchymal transition (EMT) following transformation acquire presence of TILs and IFN/STAT signaling, and patients with CSC properties. These mesenchymal/CSCs have a significantly re- immune-responsive tumors have a decreased incidence of re- pressed IFN/STAT gene expression signature and an enhanced ability currence (3, 4, 12). In contrast, TNBCs classified as immune- to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) repressed lack TILs and evidence of IFN/STAT signaling, are led to a less aggressive epithelial/non–CSC-like state, with repressed more refractory to chemotherapy, and more likely to recur. expression of mesenchymal proteins (VIMENTIN, SLUG), reduced mi- There are three different types of IFNs: Type I (IFNs α and β) gration and tumor sphere formation, and reexpression of CD24 (a Type II (IFN-γ), and Type III (IFN-λ) (13). First identified for their surface marker for non-CSCs), concomitant with an epithelium-like ability to interfere with viral and bacterial replication, the IFNs are morphology. The CSC-like properties were correlated with high lev- also potent immune-modulatory proteins (13, 14). Type I IFNs (α, els of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), β) have been most extensively studied in a variety of cancers for which was previously linked to resistance to DNA damage. Inhibiting their antiproliferative and proapoptotic activities, including breast the expression of IRF9 (the DNA-binding component of U-ISGF3) re- cancer (13). Type I IFNs bind to their receptors (IFNAR1/2) duced the migration of mesenchymal/CSCs. Here we report a posi- and activate the receptor-associated kinases JAK1 and TYK2, tive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune re- Significance sponse linked with tumor-infiltrating lymphocytes (TILs), and a re- pressed CSC metagene signature. Taken together, our findings Current cancer therapies fail to repress tumor recurrence and me- indicate that repressed IFN signaling in TNBCs with CSC-like proper- tastasis in triple-negative breast cancer (TNBC) because they fail to ties is due to high levels of U-ISGF3 and that treatment with IFN-β target cells that possess epithelial–mesenchymal (E-M) plasticity reduces CSC properties, suggesting a therapeutic strategy to treat and acquire cancer stem cell (CSC) properties. Identifying and en- drug-resistant, highly aggressive TNBC tumors. gaging signaling pathways that regulate E-M/CSC plasticity within TNBC therefore remains an unmet critical clinical need. Recent ev- triple-negative breast cancer | cancer stem cells | interferon-beta | idence demonstrates that presence of E-M/CSC plasticity in TNBC tumor microenvironment correlates with a repressed interferon/STAT gene signature. Our data demonstrate that exogenous IFN-β targets and represses E-M/ CSC plasticity by reengaging type I IFN signaling in CSC. Our find- riple-negative breast cancer (TNBC), defined by its lack of ings have clinical relevance, as IFN-β signaling correlates with im- estrogen receptor and progesterone receptor expression and T proved patient survival and repressed CSC in TNBC. Thus, our work HER2 amplification, remains the most lethal subtype of breast suggests a therapeutic use for IFN-β in the repression of E-M/CSC– cancer (1–4). Metastasis and tumor recurrence are responsible driven tumor recurrence and metastasis in TNBC. for the majority of deaths in TNBC (1, 5, 6). Highly metastatic TNBC tumors are often composed of cells harboring epithelial– Author contributions: M.R.D., H.C., D.J.J., G.R.S., and M.W.J. designed research; M.R.D. mesenchymal (E-M) plasticity, whereby cancer cells reversibly and D.J.J. performed research; S.V., M.L.T., and J.M.F. contributed prECOG 0105 phase II express epithelial or mesenchymal proteins (7–9). Importantly, clinical trial microarray datasets; M.R.D., H.C., D.J.J., S.V., V.V., G.R.S., and M.W.J. analyzed our laboratory, along with others, has demonstrated that E-M data; V.V. wrote methods describing bioinformatic analyses of prECOG0105 tumor data- plasticity can lead to the emergence of highly migratory, mes- set; and M.R.D., H.C., G.R.S., and M.W.J. wrote the paper. enchymal cancer stem cells (Mes/CSCs) (8–10). In TNBC pa- Reviewers: S.A.M., The University of Texas MD Anderson Cancer Center; and R.R.W., The tients, standard-of-care chemotherapy effectively debulks the University of Chicago. primary tumors by eliminating the more proliferative epithelial The authors declare no conflict of interest. cells, referred to here as epithelial/non-CSCs (Ep/non-CSCs), This open access article is distributed under Creative Commons Attribution-NonCommercial- because they often lack aggressive CSC properties. In contrast, NoDerivatives License 4.0 (CC BY-NC-ND). chemotherapy often fails to target the more slowly growing Mes/ Data deposition: The microarray data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession CSCs (10). Identifying the signaling pathways that regulate no. GSE106782). plasticity in TNBC has the potential to provide therapeutic op- 1To whom correspondence may be addressed. Email: [email protected], [email protected], or tions for this difficult disease. [email protected]. Emerging evidence suggests that E-M/CSC plasticity is influ- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. enced by the tumor microenvironment (TME). Tumors consist 1073/pnas.1713728114/-/DCSupplemental. 13792–13797 | PNAS | December 26, 2017 | vol. 114 | no. 52 www.pnas.org/cgi/doi/10.1073/pnas.1713728114 Downloaded by guest on September 30, 2021 resulting in phosphorylation of cytoplasmic STAT1 and STAT2. Ep MES Ep MES Ep/non-CSC MES/CSC A B C 100% 0.1% Phosphorylated STAT1 and STAT2 bind to IRF9 to form phos- ECADHERIN phorylated IFN-stimulated gene factor 3 (P-ISGF3), the major VIMENTIN B-ACTIN 0% 97% transcription factor complex that drives the expression of hundreds CD24 STAT1 STAT2 IRF9 D E F CD44 of IFN-stimulated genes (ISGs). The , ,and 220 0 200 Ep/non-CSC genes are themselves targets of P-ISGF3, resulting in elevated levels 180 NANOG -0.5 Ep/non-CSC 160 MES/CSC of newly synthesized STAT1, STAT2, and IRF9 proteins, which, -1.0 140 B-ACTIN 120 even without tyrosine phosphorylation, form the related complex, -1.5 100 *** G IRF1 Ep MES -2.0 80 CXCL10 -2.5 MES/CSC 60 unphosphorylated-ISGF3 (U-ISGF3), which can persist for days Log Fraction ISG15 40 IFI44 -3.0 P=8.5e-23 20 following an initial exposure to IFN, resulting in prolonged ex- IFIH1 0 Number Migrated Cells without Tumorspheres 0 10 20 30 40 50 IFIT1 Number Cells Seeded 0 4 8 12162024283236404448 pression of a subset of ISGs. An effective antitumorigenic response IFIT2 Time (hours) IFITM1 to IFN requires the ability to generate a full transcriptional response IFITM2 MX1 HLIJK M following robust P-ISGF3 activation. Unbalanced IFN signaling, IFI16 STAT1 STAT2 IRF9 IRF1 SOCS1 OAS2 IFI27 1.2 1.2 IFI30 1.2 1.0 1.0 1.0 involving a high level of U-ISGF3, engages an IFN-related DNA IFIT3 1.0 1.0 1.0 0.8 0.8 0.8 IRGM 0.8 0.8 0.8 damage resistance gene signature (IRDS)thatprotectstumorcells PSME1 ** 0.6 0.6 0.6 PHYIN1 0.6 0.6 0.6 *** *** *** STAT1 0.4 0.4 0.4 0.4 0.4 from DNA-damaging chemotherapy and radiation, resulting in STAT2 0.4 *** IRF9 0.2 0.2 0.2 0.2 0.2 0.2 *** therapeutic resistance and poor prognosis in a variety of cancers, IFN Gene Signature Responsive OAS1 0 0 0 0 OAS2 0 0 Ep/non-CSC including TNBC (15, 16). Our laboratory previously demonstrated OAS3 Fold-Change Expression SOCS1 MES/CSC that even a very low level of IFN-β is sufficient to generate U-ISGF3– >2 <2 mediated transcription of genes that correspond to the IRDS (17).
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